Spirocyclic dihydro-thiazine and dihydro-oxazine bace inhibitors, and compositions and uses thereof

ABSTRACT

Compounds are provided having a structure according to Formula (I): wherein A 1 , A 2 , A 3 , Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p are defined herein. Further provided are pharmaceutical compositions including the compounds provided and methods of making and using the compounds and compositions as provided, e.g., in the treatment and prevention of various disorders, such as Alzheimer&#39;s disease.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/613,377, filed on Mar. 20, 2012, and 61/727,248, filed on Nov.16, 2012 the entirety of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Beta-secretase 1 (also known as beta-site amyloid precursor proteincleaving enzyme 1, BACE1, memapsin-2 and aspartyl protease 2) cleavesamyloid precursor protein (APP) to form an extracellular fragment(sAPPβ) and a 99 amino acid residue cell membrane bound fragment (CTFβ).The CTFβ fragment is further processed by gamma-secretase to formamyloid-β peptides of either 40 amino acids (Aβ-40) or 42 amino acids(Aβ-42). These amyloid-β peptides are involved in Alzhiemer's diseasepathology, with Aβ-42 considered the more detrimental species. Inmutations of APP that are associated with Alzheimer's disease, theproduction of Aβ-42 is increased relative to Aβ-40. Aβ peptides are alsorelevant to the processing of tau. Alzheimer's disease, a common form ofdementia, is a progressive degenerative disease that is characterized bytwo major pathologic observations in the brain which are (1)neurofibrillary tangles, which are aggregates of hyperphosphorylated tauproteins, and (2) amyloid-β plaques, which form from insolubleaggregates of amyloid-β peptides. See, for example, O'Brien and Wong,Annual Review of Neuroscience 2011, 34:185-204. The disease results inmemory loss and impaired cognitive ability, and current therapy islimited to treating the symptoms. The inhibition of BACE1 is considereda desirable pharmaceutical target, as inhibition of BACE1 is likely toslow the progression of diseases resulting in β-amyloidosis, such asAlzheimer's disease.

An extra copy of chromosome 21 is found in individuals with Downsyndrome. This chromosome contains the gene encoding APP, as well as thegene encoding BACE2 (a closely related homolog to BACE1). Down syndromepatients tend to develop Alzheimer's disease at an early age. Theadditional APP gene is believed to result in overexpression of APPresulting in an increase in Aβ peptides, which could explain the earlyonset of Alzheimer's disease in these individuals. As such, inhibitionof BACE1 is considered a desirable pharmaceutical target in treatingDown syndrome (Jiang et al., PNAS Jan. 26, 2010, 107(4):1630-1635).

Beta-secretase 2 (BACE2) is expressed in the pancreas, and is believedto be involved in the processing of pancreatic β-cells and may have arole in diabetes-associated amyloidogenesis. See, for example, Esterhazyet al, Cell Metab. 2011, Sep. 7, 14(3):365-77; and Finzi et al.,Ultrastructural Pathology 2008, November-December, 32(6):246-51. Theinhibition of BACE2 is considered a desirable pharmaceutical target, forexample in the treatment of type 2 diabetes.

A number of other diseases involve β-amyloidosis, or are otherwisedesirable targets for treatment with an inhibitor of BACE1 and/or BACE2.These include amyotrophic lateral sclerosis (Rabinovich-Toidman et al.,Neurodegenerative Disease 2012, Jan. 21; Koistinen et al., Muscle Nerve2006, October, 34(4):444-50), cerebral amyloid angiopathy (Blaise etal., The Aging Cell 2012, Jan. 19; Zipfel et al., Stroke 2009, March,40(3 Suppl):S16-S19), retinal diseases, such as glaucoma and age-relatedmacular degeneration (Guo et al., PNAS 2007, Aug. 14,104(33):13444-13449; Bruban et al., Adv Exp Med Biol. 2012, 723:67-74;Ding et al., PNAS 2011, Jul. 12, 108(28):E279-E287), cardiovascularrelated disorders, such as cardiac arrest, stroke, or ischemia(Zetterberg et al., PLoS ONE 2011, 6(12):e28263; Xiong et al.,Neurobiology of Disease 2008, 32:433-441; Wen et al., Brain Research2004, May 29, 1009(1-2):1-8), disorders involving demyelination, such asnerve injury, spinal cord injury, and multiple sclerosis (Farah et al.,The Journal of Neuroscience, 2011, Apr. 13, 31(15):5744-5754), andinclusion body myositis (Jin et al., American Journal of PathologyDecember 1998, 153(6):1679-1686; Nogalska et al., Neurosci. Lett. 2010,May 3, 474(3):140-143).

Alzheimer's disease affects a large population of elderly people, andthere are few options available at this time to combat this disease. Assuch, a considerable effort has been made to find a suitable BACE1inhibitor. For example, BACE1 and/or BACE2 inhibitors are described in alarge number of patent applications, including PCT publication numbersWO 2012057247, WO 2012057248, WO 2012147762, WO 2012147763, WO2011071135, WO 2011071057, WO 2011070781, WO 2011069934, WO 2011058763,WO 2011005738, and WO 2009134617, US patent application publicationnumbers US 2010190279, US 2010160290, US 2010093999, US 20100075957, US2009209755, US 2009082560, and US 20070287692, and U.S. Pat. No.7,964,594, U.S. Pat. No. 7,759,353, and U.S. Pat. No. 7,592,348. Onesuch BACE1 inhibitor has been tested in human clinical trials (May etal., Journal of Neuroscience, 2011, Nov. 16, 31(46):16507-16516).

In spite of considerable effort from several companies to find asuitable BACE1 inhibitor, few have made it into the clinic. Thereremains a need to find a suitable BACE1 inhibitor that ispharmaceutically active in the brain without unwanted side effects.

SUMMARY OF THE INVENTION

In one aspect, a compound is provided having a structure according toFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Y is O or S;    -   L is selected from the group consisting of a direct    -   bond, —CR⁷R⁸—, —C(O)—, —O—, —S(O)_(z)—, —NR⁹—, —CR⁷R⁸—CR¹⁰R¹¹—,        —CR⁷R⁸—C(O)—, —CR⁷R⁸—O—, —CR⁷R⁸—S(O)_(z)—, —CR⁷R⁸—NR⁹—,        —C(O)—CR¹⁰R¹¹—, —C(O)—O—, —C(O)—NR⁹—, —O—CR¹⁰R¹¹—, —O—C(O)—,        —S(O)_(z)—CR¹⁰R¹¹—, —S(O)₂—NR⁹—, —NR⁹—CR¹⁰R¹¹—, —NR⁹—C(O) and        —NR⁹—S(O)₂—;    -   A₁ is a C₃₋₁₀ carbocyclic ring or a 3 to 10 membered        heterocyclic ring;    -   A₂ is phenyl, naphthyl or a heteroaryl ring;    -   A₃ is phenyl, naphthyl or a heteroaryl ring;    -   R¹ is hydrogen, C₁₋₆ alkyl, or combines with R² to form a fused        monocyclic C₃₋₇ carbocyclic ring or 3 to 7 membered heterocyclic        ring;    -   R² and R³ are independently hydrogen or halogen, or R³ is        hydrogen and R² combines with R¹ to form a fused monocyclic C₃₋₇        carbocyclic ring or a 3 to 7 membered heterocyclic ring;    -   R⁴ at each occurrence is independently selected from the group        consisting of halogen, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, —OH, ═O, —OR¹², —S(O)_(z)R¹²,        —C(O)R¹², —NR¹³R¹⁴, and ═NR¹⁴, wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl are optionally        substituted with one or more fluoro, —OH, —NH₂, —OR^(a),        —S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b), or        optionally fluoro substituted C₃₋₆ cycloalkyl;    -   R⁵ and R⁶ at each occurrence are independently selected from the        group consisting of halogen, —CN, —OH, —NH₂, —NO₂, —C(O)—OH,        —C(O)—NH₂, —S(O)₂—NH₂, and L₁-R¹⁵;    -   R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently selected from the        group consisting of hydrogen and C₁₋₆ alkyl;    -   L₁ at each occurrence is independently selected from the group        consisting of a direct    -   bond, —C(O)—, —O—, —S(O)_(z)—, —NR¹⁶—, —C(O)—O—, —O—C(O)—,        —C(O)—NR¹⁶—, —NR¹⁶—C(O)—, —S(O)₂—NR¹⁶—, and —NR¹⁶—S(O)₂—;    -   R¹² at each occurrence is independently selected from the group        consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆        cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        and C₃₋₆ cycloalkyl are optionally substituted with one or more        substituents independently selected from the group consisting of        fluoro, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NHR^(a), —NR^(a)R^(b), and optionally fluoro substituted C₃₋₆        cycloalkyl;    -   R¹³ and R¹⁴ at each occurrence are independently selected from        the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₃₋₆ cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl, are optionally        substituted with one or more substituents independently selected        from the group consisting of    -   fluoro, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NHR^(a), —NR^(a)R^(b), and optionally fluoro substituted C₃₋₆        cycloalkyl, or R¹³ and R¹⁴ combine with the nitrogen to which        they are attached to form a 4-7 membered monocyclic heterocyclic        ring or a 5 or 7 membered heteroaryl ring, wherein said ring is        optionally substituted with one or more substituents        independently selected from the group consisting of halogen,        —CN, ═O, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NHR^(a), —NR^(a)R^(b), optionally fluoro substituted C₁₋₆        alkyl, optionally fluoro substituted C₂₋₆ alkenyl, optionally        fluoro substituted C₂₋₆ alkynyl, and optionally fluoro        substituted C₃₋₆ cycloalkyl;    -   R¹⁵ at each occurrence is independently selected from the group        consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆        cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, naphthyl, and        heteroaryl, wherein phenyl, naphthyl, and heteroaryl are        optionally substituted with one or more substituents        independently selected from the group consisting of —CN, —OH,        —NO₂, —C(O)—OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆        cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6        membered    -   heteroaryl, —OR¹⁷, —S(O)_(z)R¹⁷, —NR¹⁸R¹⁹, —C(O)R¹⁷, —C(O)—OR¹⁷,        —O—C(O)R¹⁷, —C(O)—NR¹⁸R¹⁹, —NR¹⁶—C(O)R¹⁷, —S(O)₂—NR¹⁸R¹⁹, and        —NR¹⁶—S(O)₂R¹⁷, and wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, and 3-7 membered heterocycloalkyl, as        R¹⁵ or as a substituent of phenyl, naphthyl, or heteroaryl, are        optionally substituted with one or more substituents        independently selected from the group consisting of fluoro, —CN,        —OH, ═O, ═NH, —NO₂, —C(O)—OH, C₃₋₆ cycloalkyl, 3-7 membered        heterocycloalkyl, —OR¹⁷, —S(O)_(z) ¹⁷, ═NR¹⁷, —NR¹⁸R¹⁹,        —C(O)R¹⁷, —C(O)—OR¹⁷, —O—C(O)R¹⁷, —C(O)—NR¹⁸R¹⁹, —NR¹⁶—C(O)R¹⁷,        —S(O)₂—NR¹⁸R¹⁹, and —NR¹⁶—S(O)₂R¹⁷;    -   R¹⁶ at each occurrence is independently selected from the group        consisting of hydrogen and C₁₋₆ alkyl;    -   R¹⁷ at each occurrence is independently selected from the group        consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆        cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        and C₃₋₆ cycloalkyl are optionally substituted with one or more        substituents independently selected from the group consisting of        fluoro, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NHR^(a), —NR^(a)R^(b), and optionally fluoro substituted C₃₋₆        cycloalkyl;    -   R¹⁸ and R¹⁹ at each occurrence are independently selected from        the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₃₋₆ cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl are optionally        substituted with one or more substituents independently selected        from the group consisting of    -   fluoro, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NHR^(a), —NR^(a)R^(b), and optionally fluoro substituted C₃₋₆        cycloalkyl, or R¹⁸ and R¹⁹ combine with the nitrogen to which        they are attached to form a 4-7 membered monocyclic heterocyclic        ring or a 5 or 7 membered heteraoryl ring, wherein said ring is        optionally substituted with one or more substituents        independently selected from the group consisting of halogen,        —CN, ═O, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NHR^(a), —NR^(a)R^(b), optionally fluoro substituted C₁₋₆        alkyl, optionally fluoro substituted C₂₋₆ alkenyl, optionally        fluoro substituted C₂₋₆ alkynyl, and optionally fluoro        substituted C₃₋₆ cycloalkyl;    -   R^(a) and R^(b) at each occurrence are independently selected        from the group consisting of optionally fluoro substituted C₁₋₆        alkyl, optionally fluoro substituted C₂₋₆ alkenyl, optionally        fluoro substituted C₂₋₆ alkynyl, and optionally fluoro        substituted C₃₋₆ cycloalkyl, or R^(a) and R^(b) combine with the        nitrogen to which they are attached to form        N-linked-heterocycloalkyl;    -   m is 0, 1 or 2;    -   n is 0, 1, 2 or 3;    -   p is 0, 1, 2 or 3; and    -   z is 0, 1 or 2.

In one aspect, a compound as provided herein is an inhibitor of BACE,including BACE1 and/or BACE2. The provided compound is useful for thetreatment of a variety of diseases, including, but not limited to,Alzheimer's disease, Parkinson's disease, Down syndrome, glaucoma,age-related macular degeneration, cerebral amyloid angiopathy,amyotrophic lateral sclerosis, multiple sclerosis, nerve injury, spinalcord injury, cardiac arrest, stroke, ischemia, inclusion body myositisand type 2 diabetes. Also provided is a pharmaceutical compositioncomprising a compound of Formula I, and a method of utilizing thecomposition in the treatment and prevention of various diseases.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims. Reference to compounds as described herein (e.g. a compound ofFormula I), includes reference to Formula I including any sub-genericembodiments thereof, e.g. Formula Ia, Ib or Ic (including allsub-generic embodiments thereof). Similarly, reference to compounds ofFormula II or Formula III includes reference to any subgenericembodiments thereof, e.g. Formula IIa, IIb, or IIc and Formula IIIA-IIIhrespectively (including all sub-generic embodiments thereof). Throughoutthe specification and the appended claims, a given formula or name shallencompass all isomers thereof, such as stereoisomers (e.g.diastereomers, enantiomers, atropisomers), geometrical isomers,tautomers, and mixtures thereof where such isomers exist, unless thedescription designates a specific isomer.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a”, “an”, and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes acomposition containing a single compound, as well as a compositioncontaining a mixture of two or more compounds. It should also be notedthat the term “or” is generally employed in its sense including “and/or”unless the content clearly dictates otherwise.

Compounds were named using ChemDraw Ultra v. 10.0, (available fromCambridgesoft at 100 Cambridge Park Drive, Cambridge, Mass. 02140).Alternatively, the names were generated based on the IUPAC rules or werederived from names originally generated using the aforementionednomenclature programs. In any instance where there may be any ambiguitybetween a name given to a compound structure, or if no name is providedfor a given structure, the provided structure is intended to clearlydefine the compound, and those compounds only described by the givenstructure can be readily named using the above methods, or other methodsknown to one skilled in the art.

Where multiple substituents are indicated as being attached to astructure, those substituents are independently selected unlessotherwise indicated. For example “(R⁵)_(n)” indicates R⁵ is an optionalsubstituent (n=0, 1, 2, or 3) of ring A₂, and when n is 2 or 3 R⁵groups, each R⁵ is independently selected from the Markush group ofoptions (i.e., can be the same or different than another R⁵ substituentof the ring, e.g. when n is 2, both R⁵ could be independently halogen;both R⁵ could be independently C₁₋₆ alkyl; one R⁵ could be halogen,while the other R⁵ could be C₁₋₆ alkyl, etc.). It is understood that forany optionally substituted group, any such substitution results in astable molecule. Similarly, when different R groups are described ashaving the same Markush group of options, each R is independentlyselected from the Markush group of options. For example “R⁷, R⁸, R⁹, . .. are independently selected from the group consisting of hydrogen andC₁₋₆ alkyl” means that R⁷ is independently hydrogen or any C₁₋₆ alkylgroup, R⁸ is independently hydrogen or any C₁₋₆ alkyl group, etc.Similarly, where a designated R group is used in more than one Markushgroup member, for example R¹⁷ in —OR¹⁷ or —S(O)_(Z)R¹⁷, it is understoodthat each occurrence of R¹⁷ is independently selected from the Markushgroup of options. As such, these R group definitions can be readilynarrowed independently in a subsequent dependent claim.

The term “alkyl”, by itself or as part of another substituent, means astraight or branched chain, saturated hydrocarbon radical having thenumber of carbon atoms as indicated. For example, “C₁₋₆ alkyl” means astraight or branched chain, saturated hydrocarbon radical having from 1to 6 carbon atoms and “C₁₋₃ alkyl” means a straight or branched chainsaturated hydrocarbon radical having from 1 to 3 carbon atoms. The alkylgroup includes di- and multivalent radicals. For example, the alkylgroup includes alkylene wherever appropriate, e.g., when the formulaindicates that the alkyl group is divalent or when substituents arejoined to form a ring. Examples of alkyl radicals include, but are notlimited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl,iso-butyl, sec-butyl, as well as homologs and isomers of, for example,n-pentyl or n-hexyl. Where it is indicated that alkyl is optionallysubstituted with one or more substituents, typically 1, 2, 3, 4, or 5,also 1, 2, 3, or 4, also 1, 2, or 3, also 1 or 2, or one, hydrogenatom(s) are replaced with an indicated substituent, where multiplesubstituents are independently selected unless indicated otherwise. Itis understood that any substitutions of alkyl, or alkyl substituted onanother moiety, are attached at any available atom to provide a stablecompound.

The term “alkenyl”, by itself or as part of another substituent means astraight or branched chain, hydrocarbon radical that is unsaturated orpolyunsaturated so as to have one, two or three double bonds, and havingthe number of carbon atoms as indicated. For example “C₂₋₆ alkenyl”means a straight or branched chain, hydrocarbon radical having from 2 to6 carbon atoms and having one, two or three double bonds. Exemplary C₂₋₆alkenyl includes vinyl, 2-propenyl, 1-but-3-enyl, crotyl,2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), 2-isopentenyl,1-pent-3-enyl, 1-hex-5-enyl and the like. Where it is indicated thatalkenyl is optionally substituted with one or more substituents,typically 1, 2, 3, 4, or 5, also 1, 2, 3, or 4, also 1, 2, or 3, also 1or 2, or one, hydrogen atom(s) are replaced with an indicatedsubstituent, where multiple substituents are independently selectedunless indicated otherwise. It is understood that any substitutions ofalkenyl, or alkenyl substituted on another moiety, are attached at anyavailable atom to provide a stable compound.

The term “alkynyl”, by itself or as part of another substituent means astraight or branched chain, hydrocarbon radical that is unsaturated orpolyunsaturated so as to have one, two or three triple bonds, and havingthe number of carbon atoms as indicated. For example “C₂₋₆alkynyl” meansa straight or branched chain, hydrocarbon radical having from 2 to 6carbon atoms and having one, two or three triple bonds. Exemplary C₂₋₆alkynyl includes prop-1-ynyl, prop-2-ynyl (i.e., propargyl), ethynyl and3-butynyl. Where it is indicated that alkynyl is optionally substitutedwith one or more substituents, typically 1, 2, 3, 4, or 5, also 1, 2, 3,or 4, also 1, 2, or 3, also 1 or 2, or one, hydrogen atom(s) arereplaced with an indicated substituent, where multiple substituents areindependently selected unless indicated otherwise. It is understood thatany substitutions of alkynyl, or alkynyl substituted on another moiety,are attached at any available atom to provide a stable compound.

The terms “alkoxy”, “alkylamino”, “dialkylamino”, “alkylthio”,“alkylsulfinyl”, or “alkylsulfonyl” are used in their conventionalsense, and refer to substituted or unsubstituted alkyl groups asdescribed herein above, having the number of carbon atoms as indicated,that are attached to the remainder of the molecule via an oxygen atom,an amino group, a sulfur atom, S(O) or S(O)₂, respectively. For example,“C₁₋₆alkylamino” refers to an amino group substituted with one C₁₋₆alkyl group and “di-C₁₋₆alkylamino” refers to an amino group substitutedindependently with two C₁₋₆alkyl groups. Where it is indicated that analkyl group within alkoxy, alkylamino, etc. is optionally substitutedwith one or more substituents, typically 1, 2, 3, 4, or 5, also 1, 2, 3,or 4, also 1, 2, or 3, also 1 or 2, or one, hydrogen atom(s) arereplaced with an indicated substituent, where multiple substituents areindependently selected unless indicated otherwise. It is understood thatany substitutions of alkoxy, alkylamino, etc., or alkoxy, alkylamino,etc. substituted on another moiety, are attached at any available atomto provide a stable compound.

The term “N-linked-heterocycloalkyl”, by itself or as part of anothersubstituent, means the group —NR′R″, where R′ and R″ combine with thenitrogen to form a 5-7 membered heterocycloalkyl, where theheterocycloalkyl optionally contains an additional heteroatom within thering, such as O, N, or S, and optionally is further substituted withC₁₋₆ alkyl. The ring is bound to the group it is a substituent of viathe nitrogen. Examples of N-linked-heterocycloalkyl include, but are notlimited to, piperidine, piperazine, 4-methylpiperazine, morpholine, andthiomorpholine. Where it is indicated that N-linked-heterocycloalkyl isoptionally substituted with one or more substituents, typically 1, 2, 3,4, or 5, also 1, 2, 3, or 4, also 1, 2, or 3, also 1 or 2, or one,hydrogen atom(s) are replaced with an indicated substituent, wheremultiple substituents are independently selected unless indicatedotherwise. It is understood that any substitutions ofN-linked-heterocycloalkyl, or N-linked-heterocycloalkyl substituted onanother moiety, are attached at any available atom to provide a stablecompound.

The term “carbocyclic” as used herein in describing a fused ring, meansa monocyclic saturated or partially unsaturated, non-aromatic ring or abicyclic saturated or partially unsaturated ring, wherein the bicyclicring system is non-aromatic, wherein all of the ring atoms are carbon,and having the number of ring carbon atoms as indicated. For example aC₃-C₁₀ carbocyclic ring is a monocyclic or bicyclic ring having 3 to 10carbon ring atoms and a monocyclic C₃-C₇ carbocyclic ring is amonocyclic ring having 3 to 7 carbon ring atoms. As used herein, thecarbocyclic ring is fused to another ring system, i.e. one or two of thering carbon atoms is common to an additional ring system. For examplering A₁ of a compound of Formula I is a spirocyclic ring, as one carbonatom is shared with the core ring system. It is understood that thiscommon carbon atom of the spirocyclic ring is counted among the 3 to 10carbons of the C₃-C₁₀ carbocyclic ring, and that reference to A₁ as monoor bicyclic refers only to the fused spiro portion, i.e. the fused Spiroportion designated as A₁ can be mono or bicyclic, not including the corethiazine or oxazine ring as part of bicyclic. In the case of A₁ as abicyclic ring, the second ring (i.e. the ring portion that does notinclude the spiroatom) can be aromatic, e.g. a fused phenyl. Such aspirocyclic ring system includes, without limitation, monocyclic ringssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,cyclohexenyl, and the like as well as bicyclic rings such asbicyclo[4.1.0]heptyl, bicyclo[4.4.0]decyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.1]heptenyl, spiro[4.5]decyl, adamantyl,1,2-dihydronaphthalenyl, 1,2,3,4-tetrahydronapthalenyl, 1H-indenyl,2,3-dihydro-1H-indenyl and the like. Similarly, when R¹ and R² of acompound of Formula I combine to form a fused monocyclic C₃-C₇carbocyclic, there are two carbon atoms in common with the core ringsystem, and it is understood that both common carbon atoms of the fusedring are counted among the 3 to 7 carbons of the C₃-C₇ carbocyclic ring.Such a fused ring system includes, without limitation, monocyclic ringssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,cyclohexenyl, and the like. Where it is indicated that a carbocyclicring is optionally substituted with one or more substituents, typically1, 2, 3, 4, or 5, also 1, 2, 3, or 4, also 1, 2, or 3, also 1 or 2, orone, hydrogen atom(s) are replaced with an indicated substituent, wheremultiple substituents are independently selected unless indicatedotherwise. It is understood that any substitutions of a carbocyclicring, or carbocyclic ring substituted on another moiety, are attached atany available atom to provide a stable compound.

The term “cycloalkyl” by itself or in combination with other terms,means a monocyclic saturated or partially unsaturated, non-aromaticring, wherein all of the ring atoms are carbon, and having the number ofring carbon atoms as indicated. For example, C₃-C₆ cycloalkyl is amonocyclic ring having 3 to 6 carbon atoms. Examples of C₃-C₆ cycloalkylinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and the like. Where it isindicated that cycloalkyl is optionally substituted with one or moresubstituents, typically 1, 2, 3, 4, or 5, also 1, 2, 3, or 4, also 1, 2,or 3, also 1 or 2, or one, hydrogen atom(s) are replaced with anindicated substituent, where multiple substituents are independentlyselected unless indicated otherwise. It is understood that anysubstitutions of cycloalkyl, or cycloalkyl substituted on anothermoiety, are attached at any available atom to provide a stable compound.

The term “heterocyclic” as used herein in describing a ring, means amonocyclic saturated or partially unsaturated, non-aromatic ring or abicyclic saturated or partially unsaturated ring, wherein the bicyclicring system is non-aromatic, the mono- or bicyclic ring having, forexample, 3 to 10 members, where at least one member and up to 5 members,also 1, 2 or 3 members of the ring are heteroatoms selected from, e.g.,N, O, S, Si, B and P, also N, O and S, and the remaining ring atoms arecarbon atoms, in stable combinations known to those of skill in the art.Heterocyclic ring nitrogen, sulfur and phosphorus atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Forexample, a 3-10 membered heterocyclic ring is a monocyclic or bicyclicring having 1-5 ring atoms as heteroatoms, with the remaining ring atomsas carbon. As used herein, the heteroyclic ring may be a fused ring toanother ring system, i.e. one or two of the heterocyclic ring carbonatoms is common to an additional ring system. For example ring A₁ of acompound of Formula I is a spirocyclic ring, as one carbon atom isshared with the core ring system. It is understood that this commoncarbon atom of the spirocyclic ring is counted among the 3 to 10 membersof the heterocyclic ring. In the case of a bicyclic ring at thisposition, the second ring (i.e. the ring portion that does not includethe spiroatom) can be aromatic, e.g. a fused phenyl, pyridyl, pyrazolyl,or the like. Such a spirocyclic ring system includes, withoutlimitation, monocyclic rings such as oxirane, oxetane, tetrahydrofuran,tetrahydropyran, dihydropyran, azetidine, pyrrolidine, piperidine,tetrahydropyridine, piperazine, morpholine, thiomorpholine, and the likeas well as bicyclic rings such as oxaspiro[4.5]decyl,azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]octyl, tetrahydropyridine,tetrahydroindole, dihydrobenzothiophene, dihydrobenzofuran,tetrahydrobenzofuran and the like. Similarly, when R¹ and R² of acompound of Formula I combine to form a fused monocyclic 3 to 7 memberedheterocyclic ring, there are two carbon atoms in common with the corering system, and it is understood that both common carbon atoms of thefused ring are counted among the 3 to 7 members of the heterocyclicring. Such a fused ring system includes, without limitation, monocyclicrings such as oxirane, oxetane, tetrahydrofuran, tetrahydropyran,dihydropyran, azetidine, pyrrolidine, piperidine, tetrahydropyridine,piperazine, morpholine, thiomorpholine, and the like. A monocyclic 4-7membered heterocyclic ring as used to describe formation of a ring withtwo substituents of an amine group includes, for example, azetidine,pyrrolidine, piperidine, tetrahydropyridine, tetrahydropyrimidine,piperazine, morpholine, thiomorpholine, and the like. Where it isindicated that a heterocyclic ring is optionally substituted with one ormore substituents, typically 1, 2, 3, 4, or 5, also 1, 2, 3, or 4, also1, 2, or 3, also 1 or 2, or one, hydrogen atom(s) are replaced with anindicated substituent, or a sulfur atom is substituted with 1 or 2 ═O,where multiple substituents are independently selected unless indicatedotherwise. It is understood that any substitutions of a heterocyclicring are attached at any available atom to provide a stable compound.

The term “heterocycloalkyl”, as used herein in describing a ring, meansa monocyclic saturated or partially unsaturated, non-aromatic ringhaving the indicated number of ring atoms (members), where at least onemember and up to 3 members of the ring are heteroatoms selected from,e.g., N, O, S, Si, B and P, also N, O and S, and the remaining ringatoms are carbon atoms, in stable combinations known to those of skillin the art. Heterocycloalkyl ring nitrogen, sulfur and phosphorus atomsare optionally oxidized, and the nitrogen atom(s) are optionallyquaternized. For example “3-7 membered heterocycloalkyl” means amonocyclic heterocyclic ring having 3 to 7 members, where 1, 2, or 3members are N, O, S, Si, B or P, also N, O, or S. The point ofattachment of heterocycloalkyl to the group it is a substituent of canbe via a carbon atom or via a heteroatom. Exemplary 3-7 memberedheterocycloalkyl groups for compounds described herein (e.g. a compoundof Formula I) include morpholinyl, thiomorpholinyl, thiomorpholinylS-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, tetrahydropyranyl,piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,homopiperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,dihydropyrrolyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl,dihydrofuranyl, dihydropyranyl, tetrahydrothienyl S-oxide,tetrahydrothienyl S,S-dioxide, homothiomorpholinyl S-oxide,tetrahydropyridyl, and the like. In one example, heterocycloalkyl iscycoalkylamino. Where it is indicated that heterocycloalkyl isoptionally substituted with one or more substituents, typically 1, 2, 3,4, or 5, also 1, 2, 3, or 4, also 1, 2, or 3, also 1 or 2, or one,hydrogen atom(s) are replaced with an indicated substituent, or a sulfuratom is substituted with 1 or 2 ═O, where multiple substituents areindependently selected unless indicated otherwise. It is understood thatany substitutions of heterocycloalkyl, or heterocycloalkyl substitutedon another moiety, are attached at any available atom to provide astable compound.

The terms “phenyl” and “naphthyl” have their meaning as known in theart, i.e. a benzene and naphthylene radical, respectively. Where it isindicated that phenyl or naphthyl are optionally substituted with one ormore substituents, typically 1, 2, 3, 4, or 5, also 1, 2, 3, or 4, also1, 2, or 3, also 1 or 2, or one, hydrogen atom(s) are replaced with anindicated substituent, where multiple substituents are independentlyselected unless indicated otherwise. It is understood that anysubstitutions of phenyl or napthyl, or phenyl or napthyl substituted onanother moiety, are attached at any available atom to provide a stablecompound.

The term “heteroaryl”, as used herein means, unless otherwise stated, apolyunsaturated, monocyclic or bicyclic 5 to 10 membered aromatic moietycontaining at least one and up to 5 heteroatoms, also 1, 2 or 3heteroatoms selected from N, O, S, Si and B, also N, O and S, and theremaining ring atoms are carbon atoms, in stable combinations known tothose of skill in the art. Heteroaryl ring nitrogen and sulfur atoms areoptionally oxidized, and the nitrogen atom(s) are optionallyquaternized. A heteroaryl ring can be a single aromatic ring or a fusedbicyclic ring where the bicyclic ring system can be aromatic, or one ofthe fused rings is aromatic and the other is at least partiallysaturated. In one example, a bicyclic heteroaryl is one in which theentire fused ring system is aromatic. A bicyclic heteroaryl can have theat least one heteroatom in either of the fused rings, i.e. it can beattached to the group it is a substituent of either via a heteroatomcontaining ring or a carbon only containing ring. The point ofattachment of heteroaryl to the group it is a substituent of can be viaa carbon atom or a heteroatom (e.g. nitrogen). In one example, theheteroaryl group has from 1 to 9 carbon atoms and from 1 to 5heteroatoms selected from O, S and N. A 5 or 6 membered heteroaryl meansa monocyclic heteroryl ring having 5- or 6-members, where 1, 2, 3, or 4,also 1, 2 or 3, also 1 or 2, also one member(s) is N, O or S and theremaining members are carbon atoms. A 5 or 7 membered heteroaryl, forexample when used to describe an NRR group that forms a heteroaryl ring,means a monocyclic heteroryl ring having 5- or 7-members, where 1 memberis N, and 1, 2, or 3, also 1 or 2, also one other member(s) is N and theremaining members are carbon atoms. Non-limiting examples of 5 to 10membered heteroaryl groups include pyridyl, pyrimidinyl, quinolinyl,benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl,isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl,isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl,pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,isothiazolyl, naphthyridinyl, isochromanyl, chromanyl,tetrahydroisoquinolinyl, isoindolinyl, isobenzothienyl, benzoxazolyl,pyridopyridyl, purinyl, benzodioxolyl, triazinyl, pteridinyl,benzothiazolyl, imidazopyridyl, imidazothiazolyl, dihydrobenzisoxazinyl,benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl,benzothiopyranyl, chromonyl, chromanonyl, pyridyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. In one example,heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, thiadiazolyl, triazolyl, isoxazolyl, oxazolyl, isothiazolyl,thiazolyl, oxadiazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, andpyridyl. Where it is indicated that heteroaryl is optionally substitutedwith one or more substituents, typically 1, 2, 3, 4, or 5, also 1, 2, 3,or 4, also 1, 2, or 3, also 1 or 2, or one, hydrogen atom(s) arereplaced with an indicated substituent, where multiple substituents areindependently selected unless indicated otherwise. It is understood thatany substitutions of heteroaryl, or heteroaryl substituted on anothermoiety, are attached at any available atom to provide a stable compound.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean at least one of fluorine, chlorine, bromine andiodine.

By “haloalkyl” or “haloalkoxy” is meant an alkyl or alkoxy radical, asdefined above, wherein at least one hydrogen atom of alkyl or the alkylchain of alkoxy is replaced by a halogen atom, where typically 1, 2, 3,4, or 5, also 1, 2, 3, or 4, also 1, 2, or 3, also 1 or 2, or 1 hydrogenatom(s) is replaced by an independently selected halogen. Moretypically, 1, 2 or 3 hydrogen atoms on the same carbon are replaced with1, 2 or 3 halogen atoms. In one example, the halogen is fluorine orchlorine, also fluorine. The term “haloalkyl” or “haloalkoxy” is meantto include monohaloalkyl and polyhaloalkyl. For example, the term “C₁₋₆haloalkyl” is meant to include, but not limited to, chloromethyl,1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, perfluoroethyl, 4-chlorobutyl, and 3-bromopropyl;and the term “C₁₋₆ haloalkoxy” is meant to include, but not limited to,fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,and perfluoroethoxy. Similarly, when a group such as cycloalkyl, alkyl,alkenyl, alkoxy, alkylsulfonyl and the like is referred to as optionallyfluoro substituted, at least one hydrogen atom attached to a carbon ofsaid group is replaced by a fluorine atom, where typically 1, 2, 3, 4,or 5, also 1, 2, 3, or 4, also 1, 2, or 3, also 1 or 2, or 1 hydrogenatom(s) is replaced by a fluorine atom. For example, the term“optionally fluoro substituted C₁₋₆ alkyl” is meant to include, but notlimited to, fluoromethyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, perfluoroethyl, and the like, and “optionallyfluoro substituted C₁₋₆ alkoxy” is meant to include, but not limited to,fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,perfluoroethoxy, and the like.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N),sulfur (S), silicon (Si), boron (B) and phosphorus (P). In one example,heteroatoms are O, S and N.

By “oxo” is meant the group ═O.

As used herein, the term “aromatic ring” or “non-aromatic ring” isconsistent with the definition commonly used in the art. For example,aromatic rings include phenyl and pyridyl. Non-aromatic rings includecyclohexanes, cyclohexenes, and the like.

As used herein, the term “fused ring” means at least a second ring fusedto a first to form at least a bicyclic ring, wherein the first andsecond rings have at least 1 atom in common. For example, a fused ringwith 1 atom in common refers to a spirocyclic fused ring such as thatdescribed for ring A₁ of compounds of Formula I. Fused ring systems caninclude aromatic as well as non aromatic rings, for example naphthaleneis an example of fused 6 membered rings having 2 atoms in common, whereboth rings are aromatic, while 1,2,3,4-tetrahydronaphthalene is anexample of fused 6 membered rings having 2 atoms in common, where onering is aromatic and the other is partially saturated. A fused ring canalso have more than two atoms in common, for example bridged fused ringssuch as bicyclo[3.3.1]nonane, which is an example of fused 6 memberedrings having 3 atoms in common. Fused rings include naphthalene, indole,quinoline, chromene and the like. When a fused ring is described as partof a substituent, for example in Formula I where R¹ and R² may form afused ring, the description refers to only the portion of the resultingfused ring represented by R¹, R² and the common atoms of the existingcore ring in Formula I. As such, the description of R¹ and R² combiningto form a fused monocyclic ring means that a monocyclic ring is fused tothe existing core ring, resulting in a tricyclic ring (as the core ringis already at least bicyclic with the fused spirocyclic ring A₁).Similarly, the description of A₁ as mono or bicyclic refers only to thefused Spiro portion, i.e. the fused spiro portion designated as A₁ canbe mono or bicyclic, not including the core thiazine or oxazine ring aspart of bicyclic. For example, when ring A₁ is monocyclic and R¹ and R²do not form a ring, the entire compound of Formula I is bicyclic due tothe fusion of monocyclic Spiro ring A₁.

As used herein, the term “protecting group” as it relates to a nitrogen,oxygen, or thiol protecting group, is used as a term well known in theart of organic synthesis. For example, a nitrogen protecting groupincludes, without limitation, carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Mox or McOZ), tert-butyloxycarbonyl (Boc),9-fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl(Bn), Carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM),p-methoxyphenyl (PMP), and Tosyl (Ts); an oxygen or thiol protectinggroup includes, without limitation, Acetyl (Ac), Benzoyl (Bz), Benzyl(Bn), p-methoxybenzyl (PMB), β-methoxyethyoxymethyl (MEM),dimethoxytrityl (DMT), methoxymethyl (MOM), methoxytrityl (MMT),methylthiomethyl, pivaloyl, tetrahydropyranyl (THP), trityl (Tr),timethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS),tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS). Suchprotecting groups and their use are readily known to one of skill in theart.

As used herein, the term “selective” or “selectivity” as it relates toprotease activity, means that a compound as described herein, e.g. acompound of Formula I, is a more potent inhibitor of a particularprotease, such as BACE1, when compared to another protease. As such,selectivity of BACE1 relative to another protease can be represented asa comparison, for example, of the IC₅₀ of a compound on the proteaseactivity of BACE1 to the IC₅₀ of the compound on the protease activityof another protease. For example, a compound that is 50 fold or 50×selective for BACE1 protease activity relative to another proteaseactivity will have a ratio of IC₅₀(other protease)÷IC₅₀(BACE1)=50 (or aratio of IC₅₀(BACE1)÷IC₅₀(other protease)=0.02).

The phrase “therapeutically effective amount” as used herein means thatamount of a compound, material, or composition as described herein (e.g.a compound of Formula I and compositions thereof), which is effectivefor producing a desired therapeutic effect, at a reasonable benefit/riskratio applicable to any medical treatment. For example, a“therapeutically effective amount” is an amount effective to reduce orlessen at least one symptom of the disease or condition being treated orto reduce or delay onset of one or more clinical markers or symptomsassociated with the disease or condition, or to modify or reverse thedisease process.

The terms “treatment” or “treating” when referring to a disease orcondition, means producing a desired therapeutic effect. Exemplarytherapeutic effects include delaying onset or reducing at least onesymptom associated with the disease, positively affecting (e.g.,reducing or delaying onset) of a clinical marker associated with thedisease and slowing or reversing disease progression. Treatment includespreventative therapy, for example a subject that is at high risk ofdeveloping a disease or condition can be treated proactively to preventor delay the onset of the disease. Treatment also includes therapeutictreatment of an existing disease or condition, for example, a subjecthaving symptoms of a disease or condition can be treated to reduce orreverse the progression of the disease, or to alleviate the symptoms ofthe disease.

The term “pharmaceutically acceptable” refers to those properties and/orsubstances that are acceptable to a patient (e.g., human patient) from atoxicological and/or safety point of view.

The term “pharmaceutically acceptable salt” means any salt of a compoundas described herein, e.g. a compound of Formula I, which is preparedwith relatively nontoxic acids or bases, depending on the particularsubstituents found on a compound as described herein. A compound ofFormula I may be prepared as a pharmaceutically acceptable salt. Suchsalts and their preparation for use as pharmaceuticals are readily knownto those of skill in the art. Such salts may provide improvedproperties, e.g. solubility or pharmacokinetic properties, such that thepharmacological activity of the compound of Formula I is enhanced uponadministration to a subject. It is understood that such pharmaceuticallyacceptable salts are effectively equivalent to compounds of Formula I,i.e. when such a salt is administered into a subject, the administrationeffectively encompasses the use of a compound of Formula I.

The term “pharmaceutically acceptable solvate” means any solvate,including any hydrate, of a compound as described herein, e.g. acompound of Formula I, which is prepared with a relatively nontoxicsolvent or solvents. A compound as described herein, e.g. a compound ofFormula I, can exist in unsolvated forms as well as solvated forms,including hydrated forms. Such solvates may provide improved properties,e.g. solubility or pharmacokinetic properties, such that thepharmacological activity of the compound of Formula I is enhanced uponadministration to a subject. It is understood that such pharmaceuticallyacceptable solvated forms are effectively equivalent to compounds ofFormula I, i.e. when such a solvated form is administered into asubject, the administration effectively encompasses the use of acompound of Formula I.

The term “pharmaceutically acceptable carrier” means anypharmaceutically acceptable ingredient known to those of skill in theart, which is typically considered a non-active ingredient.

The term “pharmaceutically acceptable derivative” or “prodrug” means anyderivative of a compound of Formula I that is suitable forpharmaceutical use. For example, a prodrug of a compound as describedherein which, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound as described herein(e.g. a compound of Formula I). In some examples, a prodrug increasesthe bioavailability of a compound as described herein when such compoundis administered to a mammal (e.g., by allowing an orally administeredcompound to be more readily absorbed into the blood stream) or whichenhance delivery of the parent compound to a biological compartment(e.g., the brain) relative to the parent species. It is understood thatsuch a prodrug form is effectively equivalent to a compound of FormulaI, i.e. when such a prodrug form is administered into a subject, theadministration effectively encompasses the use of a compound of FormulaI.

The term “polymorph” refers to a crystal form of a compound as describedherein. It is understood that a compound as described herein may occurin many different crystal forms, or polymorphs, or can be made intoamorphous form (i.e. solid form without any defined crystal structure).While such varied solid forms may have different pharmaceuticalproperties, it is understood that any such crystal form comprises acompound as described herein, i.e. it is encompassed by a compound ofFormula I. Similarly, a pharmaceutically acceptable salt or solvate of acompound of Formula I may exist as polymorphs, where any such polymorphis encompassed by a pharmaceutically acceptable salt or apharmaceutically acceptable solvate of a compound of Formula I.

The term “metabolite” refers to a derivative of a compound as describedherein resulting from administering such a compound to a recipient,wherein the metabolite results from metabolic processes in the body of arecipient. In some examples, a metabolite may be pharmaceuticallyactive. Any metabolites may be identified using routine techniques knownin the art, and their biological activity assessed as described herein.

The term “conjugate” refers to a derivative of a compound as describedherein resulting in the linking of a suitable adjunct to provideadditional features or uses. A compound of Formula I may be furtherconjugated via a suitably reactive group to link a moiety to thecompound of Formula I, such that the linked moiety provides, forexample, improved targeting to certain tissues, improved transportacross the blood brain barrier, a suitable binding molecule for use as aprobe, or the like. The portion of the conjugate that is derived from acompound of Formula I is expected to have similar properties to acompound of Formula I, for example such portion of the conjugate willreadily bind to BACE1 and/or BACE2 in a similar manner to thenon-derivative compound of Formula I. Such conjugates can be used, forexample, for targeted drug delivery, improved delivery to the brain orCNS, as a probe for identifying BACE in a biological mixture or forisolating BACE from a biological mixture, or the like.

The term “isotopically enhanced” or “isotopically enhanced form” meansthat a compound as described herein, e.g. a compound of Formula I, maybe modified to contain unnatural proportions of certain atomic isotopesat one or more of the atoms that constitute such a compound. Forexample, a compound can be radiolabeled with radioactive isotopes, suchas for example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). Suchisotopic variations of a compound as described herein, whetherradioactive or not, is effectively encompassed by compounds as describedherein. For example, a compound in which one or more of the hydrogenatoms are replaced with another stable isotope of hydrogen (i.e.,deuterium) or a radioactive isotope (i.e., tritium), is expected to havesimilar activity to the compound without isotopic enhancement as itrelates to BACE inhibition, and such a compound is effectivelyequivalent to a compound of Formula I. Such an isotopically enhancedcompound may be useful, for example, in detection of the compound invivo or in biological tissue, such as a radiolabelled compoundcontaining ³H or ¹⁴C to assess tissue distribution, or a positronemitting compound containing ¹¹C, ¹⁵O, ¹³N, ¹⁸F or the like useful inpositron emission tomography for in vivo imaging. Similarly, adeuterated compound may provide a compound with greater metabolicstability than the analogous non-deuterated compound, such that thedeuterated compound has better pharmacokinetic properties. Anyisotopically enhanced compound is expected to have similar inhibitoryactivity as it relates to BACE1 and or BACE2, and other proteases, suchas Cathepsin D, Cathepsin E, Pepsin and Renin. Such a compound isreadily prepared by those of skill in the art, for example by themethods as described herein or other methods known in the art, wheresuitable isotopically enhanced reagents may be used to provide theisotopically enhanced compounds.

As used herein, the term “chiral”, “enantiomerically enriched” or“diastereomerically enriched” refers to a compound having anenantiomeric excess (ee) or a diastereomeric excess (de) of greater thanabout 50%, also greater than about 70% and also greater than about 90%.In one example, enantiomeric or diastereomeric excess is higher thanabout 90%, e.g., those compositions with greater than about 95%, greaterthan about 97% and greater than about 99% ee or de. The terms“enantiomeric excess” and “diastereomeric excess” are used in theirconventional sense. Compounds with a single stereocenter are referred toas being present in “enantiomeric excess”, those with at least twostereocenters are referred to as being present in “diastereomericexcess”. The value of ee will be a number from 0 to 100, zero beingracemic and 100 being enantiomerically pure. For example, a 90% eereflects the presence of 95% of one enantiomer and 5% of the other(s) inthe material in question. Stereoisomers are detectable if aconcentration of such stereoisomer in the analyzed mixture can bedetermined using common analytical methods, such as chiral HPLC.

The terms “use in combination”, “combination use” or the like, means useof a compound as described herein with one or more other therapeuticsfor the treatment, prevention, or amelioration of symptoms of a disease.Combination use includes use of a compound as described herein at anypoint before, during or after treatment with one or more othertherapeutic treatments, for example a compound as described herein andanother therapeutic agent can be administered essentiallysimultaneously, either in different vehicles, or can be administered inthe same vehicle (e.g. can be manufactured into the same pill, tablet,solution, etc.); or a compound as described herein can be administeredprior to (e.g. minutes, hours, days, or weeks before) administeringanother therapeutic agent; or a compound as described herein can beadministered subsequently to (e.g. minutes, hours, days, or weeks after)administering another therapeutic agent.

The term “BACE-mediated condition” or any other variation thereof, asused herein means any disease or other condition in which BACE,including BACE1 and/or BACE2 is known to play a role, or a disease statethat is associated with elevated activity or expression of BACE. Forexample, a “BACE1-mediated condition” may be relieved by inhibitingBACE1 protease activity. Such conditions include certainneurodegenerative diseases, such as Alzheimer's disease. For example, a“BACE2-mediated condition” may be relieved by inhibiting BACE2 proteaseactivity. Such conditions include certain metabolic diseases, such astype 2 diabetes.

The term “β-amyloid related condition”, or “amyloid-β relatedcondition”, “Aβ peptide related condition” or “Aβ related condition”, orany other variation thereof, as used herein mean any disease or othercondition in which abnormal Aβ peptide (e.g. increased levels of Aβpeptide, including Aβ peptide aggregation, oligomerization,fibrillization or Aβ peptide containing plaques) are causative of orimplicated in the disease, such that the disease or condition may berelieved by reduction in the production or level of Aβ peptide,including reduction in soluble Aβ levels and/or reduction in the levelsof Aβ containing plaques (β-amyloid plaques). In one example, aβ-amyloid related disease or condition is associated with Aβ peptideaggregation, oligomerization, fibrillization or plaque formation. In oneexample, a β-amyloid related condition is relieved by inhibiting BACEprotease activity, including BACE1 and/or BACE2 protease activity. Inone example, a β-amyloid related condition is relieved by inhibitingBACE1 protease activity.

The term “neurodegenerative diseases” or “neurological disease” includesany disease or condition characterized by problems with movements, suchas ataxia, and conditions affecting cognitive abilities (e.g., memory)as well as conditions generally related to all types of dementia.“Neurodegenerative diseases” may be associated with impairment or lossof cognitive abilities, potential loss of cognitive abilities and/orimpairment or loss of brain cells. Exemplary “neurodegenerativediseases” include Alzheimer's disease (including conditions associatedwith Alzheimer's disease, such as dementia, attention deficit,depression, agitation, mild cognitive impairment, cognitive decline,memory loss, senility, neurodegeneration, olfactory impairment), diffuseLewy body type Alzheimer's disease, Parkinson's disease (includingdementia associated with Parkinson's disease), frontotemporal dementiaswith parkinsonism, progressive supranuclear palsy (including dementiaassociated with supranuclear palsy), cortical basal degeneration(including dementia associated with cortical basal degeneration),dementia with Lewy bodies, presenile dementia, senile dementia,multi-infarct dementia, dementia of mixed vascular and degenerativeorigin, mild cognitive impairment, Down syndrome (including dementia andcognitive impairment associated with Down syndrome), hereditary cerebralhemorrhage with amyloidosis of the Dutch-Type, cerebral amyloidangiopathy, amyotrophic lateral sclerosis, Huntington's disease, braininjuries, as well as ischemia and stroke. “Neurodegenerative diseases”also includes any undesirable condition associated with the disease. Forinstance, a method of treating a neurodegenerative disease includesmethods of treating or preventing loss of neuronal functioncharacteristic of neurodegenerative disease.

Certain spirocyclic thiazines and oxazines, e.g. a compound as describedherein within the scope of Formula I, are potent inhibitors of BACE1and/or BACE2. In some embodiments, such a compound exhibits propertiesconducive to good CNS exposure. A compound as described herein ischaracterized by one or more of the following properties:

(i) relatively low affinity for the P-glycoprotein (In one example, thecompounds exhibit essentially no binding affinity/are not substrates forthe P-glycoprotein);(ii) relatively low molecular weight;(iii) relatively low number of H-bond donors;(iv) relatively low total polar surface area (TPSA);(v) selectivity favoring BACE1, over other proteases, particularly overCathepsin D; and(vi) appreciable solubility.

Furthermore, certain compounds as described herein are characterized byrelatively high brain to plasma ratios and good brain exposure asindicated by in vivo experimental results (e.g., see Examples B, C). Thepresently described BACE1 and/or BACE2 inhibitors provide compounds withgood CNS exposure properties and selectivity favoring BACE, in oneexample BACE1, over other proteases.

In one aspect, compounds are provided having a structure according toFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Y is O or S;    -   L is selected from the group consisting of a direct    -   bond, —CR⁷R⁸—, —C(O)—, —O—, —S(O)_(z)—, —NR⁹—, —CR⁷R⁸—CR¹⁰R¹¹—,        —CR⁷R⁸—C(O)—, —CR⁷R⁸—O—, —CR⁷R⁸—S(O)_(z)—, —CR⁷R⁸—NR⁹—,        —C(O)—CR¹⁰R¹¹—, —C(O)—O—, —C(O)—NR⁹—, —O—CR¹⁰R¹¹—, —O—C(O)—,        —S(O)_(z)CR¹⁰R¹¹—, —S(O)₂—NR⁹—, —NR⁹—CR¹⁰R¹¹—, —NR⁹—C(O)—, and        —NR⁹— S(O)₂—;    -   A₁ is a C₃₋₁₀ carbocyclic ring or a 3 to 10 membered        heterocyclic ring;    -   A₂ is phenyl, naphthyl or a heteroaryl ring;    -   A₃ is phenyl, naphthyl or a heteroaryl ring;    -   R¹ is hydrogen, C₁₋₆ alkyl, or combines with R² to form a fused        monocyclic C₃₋₇ carbocyclic ring or a 3 to 7 membered        heterocyclic ring;    -   R² and R³ are independently hydrogen or halogen, or R³ is        hydrogen and R² combines with R¹ to form a fused monocyclic C₃₋₇        carbocyclic ring or a 3 to 7 membered heterocyclic ring;    -   R⁴ at each occurrence is independently selected from the group        consisting of halogen, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, —OH, ═O, —OR¹², —S(O)_(z)R¹²,        —C(O)R¹², —NR¹³R¹⁴, and —NR¹⁴, wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl are optionally        substituted with one or more fluoro, —OH, —NH₂, —OR^(a),        —S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b), or        optionally fluoro substituted C₃₋₆ cycloalkyl;    -   R⁵ and R⁶ at each occurrence are independently selected from the        group consisting of halogen, —CN, —OH, —NH₂, —NO₂, —C(O)—OH,        —C(O)—NH₂, —S(O)₂—NH₂, and L₁-R¹⁵;    -   R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently selected from the        group consisting of hydrogen and C₁₋₆ alkyl;    -   L₁ at each occurrence is independently selected from the group        consisting of a direct    -   bond, —C(O)—, —O—, —S(O)_(z)—, —NR¹⁶—, —C(O)—O—, —O—C(O)—,        —C(O)—NR¹⁶—, —NR¹⁶—C(O)—, —S(O)₂NR¹⁶—, and —NR¹⁶—S(O)₂—;    -   R¹² at each occurrence is independently selected from the group        consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆        cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        and C₃₋₆ cycloalkyl are optionally substituted with one or more        substituents independently selected from the group consisting of        fluoro, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NHR^(a), —NR^(a)R^(b), and optionally fluoro substituted C₃₋₆        cycloalkyl;    -   R¹³ and R¹⁴ at each occurrence are independently selected from        the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₃₋₆ cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl, are optionally        substituted with one or more substituents independently selected        from the group consisting of    -   fluoro, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NHR^(a), —NR^(a)R^(b), and optionally fluoro substituted C₃₋₆        cycloalkyl, or R¹³ and R¹⁴ combine with the nitrogen to which        they are attached to form a 4-7 membered monocyclic heterocyclic        ring or a 5 or 7 membered heteroaryl ring, wherein said ring is        optionally substituted with one or more substituents        independently selected from the group consisting of halogen,        —CN, ═O, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NR^(a)R^(b), optionally fluoro substituted C₁₋₆ alkyl,        optionally fluoro substituted C₂₋₆ alkenyl, optionally fluoro        substituted C₂₋₆ alkynyl, and optionally fluoro substituted C₃₋₆        cycloalkyl;    -   R¹⁵ at each occurrence is independently selected from the group        consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆        cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, naphthyl, and        heteroaryl, wherein phenyl, naphthyl, and heteroaryl are        optionally substituted with one or more substituents        independently selected from the group consisting of —CN, —OH,        —NO₂, —C(O)—OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆        cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6        membered    -   heteroaryl, —OR¹⁷, —S(O)_(z)R¹⁷, —NR¹⁸R¹⁹, —C(O)R¹⁷, —C(O)—OR¹⁷,        —O—C(O)R¹⁷, —C(O)—NR¹⁸R¹⁹, —NR¹⁶—C(O)R¹⁷, —S(O)₂—NR¹⁸R¹⁹, and        —NR¹⁶—S(O)₂R¹⁷, and wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, and 3-7 membered heterocycloalkyl, as        R¹⁵ or as a substituent of phenyl, naphthyl, or heteroaryl, are        optionally substituted with one or more substituents        independently selected from the group consisting of fluoro, —CN,        —OH, ═O, ═NH, —NO₂, —C(O)—OH, C₃₋₆ cycloalkyl, 3-7 membered        heterocycloalkyl, —OR¹⁷, —S(O)_(z)R¹⁷, ═NR¹⁷, —NR¹⁸R¹⁹,        —C(O)R¹⁷, —C(O)—OR¹⁷, —O—C(O)R¹⁷, —C(O)—NR¹⁸R¹⁹, —NR¹⁶—C(O)R¹⁷,        —S(O)₂—NR¹⁸R¹⁹, and —NR¹⁶—S(O)₂R¹⁷;    -   R¹⁶ at each occurrence is independently selected from the group        consisting of hydrogen and C₁₋₆ alkyl;    -   R¹⁷ at each occurrence is independently selected from the group        consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆        cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        and C₃₋₆ cycloalkyl are optionally substituted with one or more        substituents independently selected from the group consisting of        fluoro, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NHR^(a), —NR^(a)R^(b), and optionally fluoro substituted C₃₋₆        cycloalkyl;    -   R¹⁸ and R¹⁹ at each occurrence are independently selected from        the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₃₋₆ cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, and C₃₋₆cycloalkyl are optionally        substituted with one or more substituents independently selected        from the group consisting of    -   fluoro, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NR^(a)R^(b), and optionally fluoro substituted C₃₋₆ cycloalkyl,        or R¹⁸ and R¹⁹ combine with the nitrogen to which they are        attached to form a 4-7 membered monocyclic heterocyclic ring or        a 5 or 7 membered heteraoryl ring, wherein said ring is        optionally substituted with one or more substituents        independently selected from the group consisting of halogen,        —CN, ═O, —OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a),        —NHR^(a), —NR^(a)R^(b), optionally fluoro substituted C₁₋₆        alkyl, optionally fluoro substituted C₂₋₆ alkenyl, optionally        fluoro substituted C₂₋₆ alkynyl, and optionally fluoro        substituted C₃₋₆ cycloalkyl;    -   R^(a) and R^(b) at each occurrence are independently selected        from the group consisting of optionally fluoro substituted C₁₋₆        alkyl, optionally fluoro substituted C₂₋₆ alkenyl, optionally        fluoro substituted C₂₋₆ alkynyl, and optionally fluoro        substituted C₃₋₆ cycloalkyl, or R^(a) and R^(b) combine with the        nitrogen to which they are attached to form        N-linked-heterocycloalkyl;    -   m is 0, 1 or 2;    -   n is 0, 1, 2 or 3;    -   p is 0, 1, 2 or 3; and    -   z is 0, 1 or 2.

In some embodiments of a compound of Formula I, Y is O. In someembodiments, Y is S.

In some embodiments of a compound of Formula I, L is a direct bond,—NR⁹—, —C(O)—NR⁹—, or —NR⁹—C(O)—. In some embodiments, L is a directbond, —NR⁹—, or —NR⁹—C(O)—. In some embodiments, L is —NR⁹ — or—NR⁹—C(O)—. In some embodiments, L is a direct bond. In someembodiments, L is —C(O)—NR⁹— or —NR⁹—C(O)—. In some embodiments, L is—C(O)—NR⁹—. In some embodiments, L is —NR⁹—C(O)—. In some embodiments, Lis —NR⁹—.

In some embodiments of a compound of Formula I, A₁ is a C₃₋₁₀carbocyclic ring. In some embodiments A₁ is a C₃₋₆ monocycliccarbocyclic ring. In some embodiments, A₁ is cyclohexane. In someembodiments, A₁ is cyclopentane. In some embodiments, A₁ is cyclobutane.In some embodiments, A₁ is cyclopropane.

In some embodiments of a compound of Formula I, A₁ is a 3 to 10 memberedheterocyclic ring. In some embodiments A₁ is a 4 to 6 memberedmonocyclic heterocyclic ring. In some embodiments A₁ is a 4 to 6membered monocyclic heterocyclic ring that contains one oxygen atom orone sulfur atom as the only heteroatom. In some embodiments A₁ is a 4 to6 membered monocyclic heterocyclic ring that contains one oxygen atom.In some embodiments A₁ is tetrahydropyran. In some embodiments A₁ istetrahydrofuran. In some embodiments A₁ is oxetane.

In some embodiments of a compound of Formula I, A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring. In some embodiments A₂ isphenyl or a monocyclic 5 membered heteroaryl ring. In some embodimentsA₂ is phenyl or thiophenyl. In some embodiments A₂ is a monocyclic 5membered heteroaryl ring. In some embodiments A₂ is thiophenyl. In someembodiments A₂ is pyrazolyl. In some embodiments A₂ is phenyl.

In some embodiments of a compound of Formula I, A₃ is phenyl, or amonocyclic 5-6 membered heteroaryl ring. In some embodiments A₃ isphenyl, oxazolyl, pyridinyl, or pyrazinyl. In some embodiments A₃ isphenyl or a monocyclic 6 membered heteroaryl ring. In some embodimentsA₃ is phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. In someembodiments A₃ is phenyl. In some embodiments A₃ is pyridinyl. In someembodiments A₃ is pyrazinyl. In some embodiments A₃ is pyrimidinyl. Insome embodiments A₃ is pyridazinyl. In some embodiments A₃ is oxazolyl.

In some embodiments of a compound of Formula I, R¹ is hydrogen or C₁₋₃alkyl. In some embodiments R¹ is methyl. In some embodiments, R¹ ishydrogen. In some embodiments, R¹ is ethyl. In some embodiments, R¹ isn-propyl. In some embodiments, R¹ is isopropyl.

In some embodiments of a compound of Formula I, R² and R³ areindependently hydrogen or halogen. In some embodiments, R² and R³ areindependently hydrogen or fluoro. In some embodiments, R² and R³ areboth hydrogen or both fluoro. In some embodiments, R² and R³ are bothhydrogen. In some embodiments, R² and R³ are both halogen. In someembodiments, R² and R³ are both fluoro.

In some embodiments of a compound of Formula I, R⁴ is halogen. In someembodiments, R⁴ is fluoro. In some embodiments, R⁴ is fluoro and m is 1or 2. In some embodiments, R⁴ is fluoro and m is 2. In some embodiments,R⁴ is fluoro, m is 2, and both fluoro are attached to the same carbonatom. In some embodiments, m is 0. In some embodiments, R⁴ is —C(O)CH₃.In some embodiments, R⁴ is —C(O)CH₃ and m is 1.

In some embodiments of a compound of Formula I, Y is O or S; L is adirect bond, —C(O)—NR⁹—, or —NR⁹—C(O)—; A₁ is a C₃₋₁₀ carbocyclic ring,in some embodiments a C₃₋₆ monocyclic carbocyclic ring or A₁ is a 3 to10 membered heterocyclic ring, in some embodiments a 4 to 6 memberedmonocyclic heterocyclic ring, in some embodiments the 4 to 6 memberedmonocyclic heterocyclic ring contains one oxygen atom or one sulfur atomas the only heteroatom; A₂ is phenyl, or a monocyclic 5-6 memberedheteroaryl ring, in some embodiments a monocyclic 5 membered heteroarylring; A₃ is phenyl, or a monocyclic 5-6 membered heteroaryl ring, insome embodiments phenyl or a monocyclic 6 membered heteroaryl ring, insome embodiments phenyl, pyridinyl, pyrazinyl, pyrimidinyl orpyridazinyl.

In some embodiments of a compound of Formula I, Y is O or S; L is adirect bond, —C(O)—NR⁹—, or —NR⁹—C(O)—; A₁ is a C₃₋₁₀ carbocyclic ring,in some embodiments a C₃₋₆ monocyclic carbocyclic ring; A₂ is phenyl, ora monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring; A₃ is phenyl, or a monocyclic 5-6membered heteroaryl ring, in some embodiments phenyl or a monocyclic 6membered heteroaryl ring, in some embodiments phenyl, pyridinyl,pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula I, Y is O or S; L is adirect bond, —C(O)—NR⁹—, or —NR⁹—C(O)—; A₁ is a 3 to 10 memberedheterocyclic ring, in some embodiments a 4 to 6 membered monocyclicheterocyclic ring, in some embodiments the 4 to 6 membered monocyclicheterocyclic ring contains one oxygen atom or one sulfur atom as theonly heteroatom; A₂ is phenyl, or a monocyclic 5-6 membered heteroarylring, in some embodiments a monocyclic 5 membered heteroaryl ring; A₃ isphenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments phenyl or a monocyclic 6 membered heteroaryl ring, in someembodiments phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula I, Y is O or S; L is adirect bond, —NR⁹—, or —NR⁹—C(O)—; A₁ is a C₃₋₁₀ carbocyclic ring, insome embodiments a C₃₋₆ monocyclic carbocyclic ring or A₁ is a 3 to 10membered heterocyclic ring, in some embodiments a 4 to 6 memberedmonocyclic heterocyclic ring, in some embodiments the 4 to 6 memberedmonocyclic heterocyclic ring contains one oxygen atom or one sulfur atomas the only heteroatom, in some embodiments, one oxygen atom as the onlyheteroatom; A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring,in some embodiments phenyl or thiophenyl; and A₃ is phenyl, or amonocyclic 5-6 membered heteroaryl ring, in some embodiments phenyl,oxazolyl, pyridinyl, or pyrazinyl.

In some embodiments of a compound of Formula I, Y is O or S; L is adirect bond, —NR⁹—, or —NR⁹—C(O)—; A₁ is a C₃₋₁₀ carbocyclic ring, insome embodiments a C₃₋₆ monocyclic carbocyclic ring; A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring, in some embodiments phenyl orthiophenyl; and A₃ is phenyl, or a monocyclic 5-6 membered heteroarylring, in some embodiments phenyl, oxazolyl, pyridinyl, or pyrazinyl.

In some embodiments of a compound of Formula I, Y is O or S; L is adirect bond, —NR⁹—, or —NR⁹—C(O)—; A₁ is a 3 to 10 membered heterocyclicring, in some embodiments a 4 to 6 membered monocyclic heterocyclicring, in some embodiments the 4 to 6 membered monocyclic heterocyclicring contains one oxygen atom or one sulfur atom as the only heteroatom,in some embodiments oxygen as the only heteroatom; A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring, in some embodiments phenyl orthiophenyl; and A₃ is phenyl, or a monocyclic 5-6 membered heteroarylring, in some embodiments phenyl, oxazolyl, pyridinyl, or pyrazinyl.

In some embodiments of a compound of Formula I, further to any of theabove embodiments, R¹ is methyl.

In some embodiments of a compound of Formula I, further to any of theabove embodiments, Y is O. In some embodiment, further to any of theabove embodiments, Y is S.

In some embodiments of a compound of Formula I, further to any of theabove embodiments, n is 0, 1 or 2, p is 0, 1 or 2, and each R⁵ and R⁶are independently selected from the group consisting of —CN, halogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylamino, alkylamino, N-linked-heterocycloalkyl, and C₃₋₆cycloalkyl, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and thealkyl chains of C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino, ordi-C₁₋₆ alkylamino are optionally substituted with one or moresubstituents independently selected from the group consisting of fluoro,—CN, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,alkylamino and N-linked-heterocycloalkyl. In some embodiments, n is 0 or1; R⁵ is halogen, —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, or C₁₋₆haloalkoxy; p is 0, 1, or 2; and R⁶ at each occurrence is independentlyselected from the group consisting of halogen, —CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino,di-C₁₋₆ alkylamino, N-linked-heterocycloalkyl, and C₃₋₆ cycloalkyl,wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and the alkyl chains ofC₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino, or di-C₁₋₆ alkylaminoas R⁶ are optionally substituted with one or more substituentsindependently selected from the group consisting of fluoro, —CN, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, alkylaminoand N-linked-heterocycloalkyl. In some embodiments, further to any ofthe above embodiments, n is 1, R⁵ is halogen, p is 0, 1 or 2, and eachR⁶ is independently selected from the group consisting of —CN, halogen,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl.

In some embodiments of a compound of Formula I, the compound has astructure according to Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   q is 0 or 1;    -   R²⁰ is selected from the group consisting of hydrogen, —OH,    -   ═O, —OR¹², —S(O)_(z)R¹², —NR¹³R¹⁴, and ═NR¹⁴; and    -   A₂, A₃, Y, R⁵, R⁶, R¹², R¹³, R¹⁴, z, n and p are as defined for        a compound of Formula I.

In some embodiments of a compound of Formula Ia, Y is O. In someembodiments, Y is S.

In some embodiments of a compound of Formula Ia, q is 0. In someembodiments q is 1.

In some embodiments of a compound of Formula Ia, L is a direct bond,—NR⁹—, —C(O)—NR⁹—, or —NR⁹—C(O)—. In some embodiments, L is a directbond, —NR⁹—, or —NR⁹—C(O)—. In some embodiments, L is —NR⁹— or—NR⁹—C(O)—. In some embodiments, L is a direct bond. In someembodiments, L is —C(O)—NR⁹— or —NR⁹—C(O)—. In some embodiments, L is—C(O)—NR⁹—. In some embodiments, L is —NR⁹—C(O)—. In some embodiments, Lis —NR⁹—.

In some embodiments of a compound of Formula Ia, A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring. In some embodiments A₂ isphenyl or a monocyclic 5 membered heteroaryl ring. In some embodimentsA₂ is phenyl or thiophenyl. In some embodiments A₂ is a monocyclic 5membered heteroaryl ring. In some embodiments A₂ is thiophenyl. In someembodiments A₂ is pyrazolyl. In some embodiments, A₂ is phenyl.

In some embodiments of a compound of Formula Ia, A₃ is phenyl, or amonocyclic 5-6 membered heteroaryl ring. In some embodiments A₃ isphenyl, oxazolyl, pyridinyl, or pyrazinyl. In some embodiments A₃ isphenyl or a monocyclic 6 membered heteroaryl ring. In some embodimentsA₃ is phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. In someembodiments A₃ is phenyl. In some embodiments A₃ is pyridinyl. In someembodiments A₃ is pyrazinyl. In some embodiments A₃ is pyrimidinyl. Insome embodiments A₃ is pyridazinyl. In some embodiments A₃ is oxazolyl.

In some embodiments of a compound of Formula Ia, R²⁰ is hydrogen. Insome embodiments, R²⁰ is —OH, ═O, or —OR¹². In some embodiments, R²⁰ is—S(O)_(z)R¹². In some embodiments, R²⁰ is —NR¹³R¹⁴, or ═NR¹⁴. In someembodiments, R²⁰ is —NR¹³R¹⁴.

In some embodiments of a compound of Formula Ia, Y is O or S; L is adirect bond, —C(O)—NR⁹—, or —NR⁹—C(O)—; A₂ is phenyl, or a monocyclic5-6 membered heteroaryl ring, in some embodiments a monocyclic 5membered heteroaryl ring; A₃ is phenyl, or a monocyclic 5-6 memberedheteroaryl ring, in some embodiments phenyl or a monocyclic 6 memberedheteroaryl ring, in some embodiments phenyl, pyridinyl, pyrazinyl,pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ia, Y is O or S; q is 0; Lis a direct bond, —C(O)—NR⁹—, or —NR⁹—C(O)—; A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring; A₃ is phenyl, or a monocyclic 5-6membered heteroaryl ring, in some embodiments phenyl or a monocyclic 6membered heteroaryl ring, in some embodiments phenyl, pyridinyl,pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ia, Y is O or S; q is 1; Lis a direct bond, —C(O)—NR⁹—, or —NR⁹—C(O)—; A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring; A₃ is phenyl, or a monocyclic 5-6membered heteroaryl ring, in some embodiments phenyl or a monocyclic 6membered heteroaryl ring, in some embodiments phenyl, pyridinyl,pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ia, Y is S, R²⁰ is H, and Lis a bond. In some embodiments Y is S; R²⁰ is H; L is a bond; A₂ isphenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments a monocyclic 5 membered heteroaryl ring; A₃ is phenyl, or amonocyclic 5-6 membered heteroaryl ring, in some embodiments phenyl or amonocyclic 6 membered heteroaryl ring, in some embodiments phenyl,pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ia, Y is O, R²⁰ is H, and Lis a bond. In some embodiments Y is O; R²⁰ is H; L is a bond; A₂ isphenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments a monocyclic 5 membered heteroaryl ring; A₃ is phenyl, or amonocyclic 5-6 membered heteroaryl ring, in some embodiments phenyl or amonocyclic 6 membered heteroaryl ring, in some embodiments phenyl,pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ia, Y is S, q is 0, R²⁰ isH, and L is a bond. In some embodiments Y is S; q is 0; R²⁰ is H; L is abond; A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring, insome embodiments a monocyclic 5 membered heteroaryl ring; A₃ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments phenylor a monocyclic 6 membered heteroaryl ring, in some embodiments phenyl,pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ia, Y is O, q is 0, R²⁰ isH, and L is a bond. In some embodiments Y is O; q is 0; R²⁰ is H; L is abond; A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring, insome embodiments a monocyclic 5 membered heteroaryl ring; A₃ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments phenylor a monocyclic 6 membered heteroaryl ring, in some embodiments phenyl,pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ia, Y is S, q is 1, R²⁰ isH, and L is a bond. In some embodiments Y is S; q is 1; R²⁰ is H; L is abond; A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring, insome embodiments a monocyclic 5 membered heteroaryl ring; A₃ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments phenylor a monocyclic 6 membered heteroaryl ring, in some embodiments phenyl,pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ia, Y is O, q is 1, R²⁰ isH, and L is a bond. In some embodiments Y is O; q is 1; R²⁰ is H; L is abond; A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring, insome embodiments a monocyclic 5 membered heteroaryl ring; A₃ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments phenylor a monocyclic 6 membered heteroaryl ring, in some embodiments phenyl,pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ia, further to any of theabove embodiments, A₂ is phenyl or thiophenyl; and A₃ is phenyl,oxazolyl, pyridinyl, or pyrazinyl.

In some embodiments of a compound of Formula I, the compound has astructure according to Formula Ib:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is O or S(O)₂;    -   r is 0, 1, or 2;    -   s is 0, 1, or 2; and    -   A₂, A₃, Y, R⁵, R⁶, n and p are as defined for a compound of        Formula I.

In some embodiments of a compound of Formula Ib, Y is O. In someembodiments, Y is S.

In some embodiments of a compound of Formula Ib, X is O. In someembodiments, X is S(O)₂.

In some embodiments of a compound of Formula Ib, L is a direct bond,—NR⁹—, —C(O)—NR⁹—, or —NR⁹—C(O)—. In some embodiments, L is a directbond, —NR⁹—, or —NR⁹—C(O)—. In some embodiments, L is —NR⁹— or—NR⁹—C(O)—. In some embodiments, L is a direct bond. In someembodiments, L is —C(O)—NR⁹— or —NR⁹—C(O). In some embodiments, L is—C(O)—NR⁹. In some embodiments, L is —NR⁹—C(O). In some embodiments, Lis —NR⁹—.

In some embodiments of a compound of Formula Ib, A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring. In some embodiments A₂ isphenyl or a monocyclic 5 membered heteroaryl ring. In some embodimentsA₂ is phenyl or thiophenyl. In some embodiments A₂ is a monocyclic 5membered heteroaryl ring. In some embodiments A₂ is thiophenyl. In someembodiments A₂ is pyrazolyl. In some embodiments, A₂ is phenyl.

In some embodiments of a compound of Formula Ib, A₃ is phenyl, or amonocyclic 5-6 membered heteroaryl ring. In some embodiments A₃ isphenyl, oxazolyl, pyridinyl, or pyrazinyl. In some embodiments A₃ isphenyl or a monocyclic 6 membered heteroaryl ring. In some embodimentsA₃ is phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. In someembodiments A₃ is phenyl. In some embodiments A₃ is pyridinyl. In someembodiments A₃ is pyrazinyl. In some embodiments A₃ is pyrimidinyl. Insome embodiments A₃ is pyridazinyl. In some embodiments A₃ is oxazolyl.

In some embodiments of a compound of Formula Ib, Y is O or S; L is adirect bond, —C(O)—NR⁹—, or —NR⁹—C(O)—; A₂ is phenyl, or a monocyclic5-6 membered heteroaryl ring, in some embodiments a monocyclic 5membered heteroaryl ring; A₃ is phenyl, or a monocyclic 5-6 memberedheteroaryl ring, in some embodiments phenyl or a monocyclic 6 memberedheteroaryl ring, in some embodiments phenyl, pyridinyl, pyrazinyl,pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ib, Y is O or S; either rand s are both 0 or r and s are both 1; L is a direct bond, —C(O)—NR⁹—,or —NR⁹—C(O)—; A₂ is phenyl, or a monocyclic 5-6 membered heteroarylring, in some embodiments a monocyclic 5 membered heteroaryl ring; A₃ isphenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments phenyl or a monocyclic 6 membered heteroaryl ring, in someembodiments phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ib, Y is O or S; r and sare both 0; L is a direct bond, —C(O)—NR⁹—, or —NR⁹—C(O)—; A₂ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring; A₃ is phenyl, or a monocyclic 5-6membered heteroaryl ring, in some embodiments phenyl or a monocyclic 6membered heteroaryl ring, in some embodiments phenyl, pyridinyl,pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ib, Y is O or S; r and sare both 1; L is a direct bond, —C(O)—NR⁹—, or —NR⁹—C(O)—; A₂ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring; A₃ is phenyl, or a monocyclic 5-6membered heteroaryl ring, in some embodiments phenyl or a monocyclic 6membered heteroaryl ring, in some embodiments phenyl, pyridinyl,pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ib, Y is O, L is a bond,and either r and s are both 0 or r and s are both 1. In some embodimentsY is O; L is a bond; either r and s are both 0 or r and s are both 1; A₂is phenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments a monocyclic 5 membered heteroaryl ring; A₃ is phenyl, or amonocyclic 5-6 membered heteroaryl ring, in some embodiments phenyl or amonocyclic 6 membered heteroaryl ring, in some embodiments phenyl,pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ib, Y is O, L is a bond,and r and s are both 0. In some embodiments Y is O; L is a bond; r and sare both 0; A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring,in some embodiments a monocyclic 5 membered heteroaryl ring; A₃ isphenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments phenyl or a monocyclic 6 membered heteroaryl ring, in someembodiments phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ib, Y is O, L is a bond,and r and s are both 1. In some embodiments Y is O; Lisa bond; r and sare both 1; A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring,in some embodiments a monocyclic 5 membered heteroaryl ring; A₃ isphenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments phenyl or a monocyclic 6 membered heteroaryl ring, in someembodiments phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ib, Y is S, L is a bond,and either r and s are both 0 or r and s are both 1. In some embodimentsY is S; L is a bond; either r and s are both 0 or r and s are both 1; A₂is phenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments a monocyclic 5 membered heteroaryl ring; A₃ is phenyl, or amonocyclic 5-6 membered heteroaryl ring, in some embodiments phenyl or amonocyclic 6 membered heteroaryl ring, in some embodiments phenyl,pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ib, Y is S, L is a bond,and r and s are both 0. In some embodiments Y is S; L is a bond; r and sare both 0; A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring,in some embodiments a monocyclic 5 membered heteroaryl ring; A₃ isphenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments phenyl or a monocyclic 6 membered heteroaryl ring, in someembodiments phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ib, Y is S, L is a bond,and r and s are both 1. In some embodiments Y is S; L is a bond; r and sare both 1; A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring,in some embodiments a monocyclic 5 membered heteroaryl ring; A₃ isphenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments phenyl or a monocyclic 6 membered heteroaryl ring, in someembodiments phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

In some embodiments of a compound of Formula Ib, further to any of theabove embodiments of Formula Ib, X is O.

In some embodiments of a compound of Formula Ib, further to any of theabove embodiments of Formula Ib, X is S(O)₂.

In some embodiments of a compound of Formula Ib, further to any of theabove embodiments, A₂ is phenyl or thiophenyl; and A₃ is phenyl,oxazolyl, pyridinyl, or pyrazinyl.

In some embodiments of a compound of Formula I, Formula Ia or FormulaIb, further to any of the above embodiments, A₂ is phenyl, thiophenyl orpyrazolyl and A₃ is pyridinyl.

In some embodiments of a compound of Formula I, Formula Ia or FormulaIb, further to any of the above embodiments, L is a direct bond, A₂ isthiophenyl or pyrazolyl and A₃ is pyridinyl.

In some embodiments of a compound of Formula I, Formula Ia or FormulaIb, further to any of the above embodiments, L is —NR⁹—C(O)—, A₂ isphenyl, and A₃ is pyridinyl.

In some embodiments of a compound of Formula I, Formula Ia or FormulaIb, further to any of the above embodiments, m is 0 or 1; R⁴ is fluoro,

═O, —OR¹², —S(O)_(z)R¹², —C(O)R¹², or —NR¹³R¹⁴, or R²⁰ is —OR¹²,—S(O)_(z)R¹², or —NR¹³R¹⁴; n is 0 or 1; R⁵ is halogen, —CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, or C₁₋₆ haloalkoxy; p is 0, 1, or 2; and R⁶at each occurrence is independently selected from the group consistingof halogen, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, andN-linked-heterocycloalkyl, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and the alkyl chains of C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆alkylamino, or di-C₁₋₆ alkylamino as R⁶ are optionally substituted withone or more substituents independently selected from the groupconsisting of fluoro, —CN, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, alkylamino and N-linked-heterocycloalkyl.

In some embodiments of a compound of Formula I, Formula Ia, or FormulaIb, further to any of the above embodiments, n is 0, 1 or 2, p is 0, 1or 2, and each R⁵ and R⁶ are independently selected from the groupconsisting of —CN, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,N-linked-heterocycloalkyl, and C₃₋₆cycloalkyl, wherein C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and the alkyl chains of C₁₋₆ alkoxy, C₁₋₆alkylsulfonyl, C₁₋₆ alkylamino, or di-C₁₋₆ alkylamino are optionallysubstituted with one or more substituents independently selected fromthe group consisting of fluoro, —CN, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆ alkylamino andN-linked-heterocycloalkyl. In some embodiments, n is 0 or 1; R⁵ ishalogen, —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, or C₁₋₆haloalkoxy; p is 0, 1, or 2; and R⁶ at each occurrence is independentlyselected from the group consisting of halogen, —CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino,di-C₁₋₆ alkylamino, N-linked-heterocycloalkyl, and C₃₋₆cycloalkyl,wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and the alkyl chains ofC₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino, or di-C₁₋₆ alkylaminoas R⁶ are optionally substituted with one or more substituentsindependently selected from the group consisting of fluoro, —CN, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆alkylamino and N-linked-heterocycloalkyl. In some embodiments, furtherto any of the above embodiments, n is 1, R⁵ is halogen, p is 0, 1 or 2,and each R⁶ is independently selected from the group consisting of —CN,halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl.

In some embodiments of a compound of Formula I, the compound has astructure according to Formula Ic:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Y₁ is O or S;    -   L₂ is selected from the group consisting of a direct bond, —NH—,        and —NH—C(O)—;    -   X₁ is a direct bond and e and f are both 1; or X₁ is CH₂, CF₂,        or O, and e and f are independently 1 or 2.    -   A₅ is phenyl or thiophenyl;    -   A₆ is phenyl, pyridinyl, pyrazinyl or oxazolyl;    -   R²² and R²³ are both hydrogen or both fluoro;    -   R²⁴ at each occurrence is independently selected from the group        consisting of —CN, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆        alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆        cycloalkyl;    -   R²⁵ at each occurrence is independently selected from the group        consisting of —CN, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino,        di-C₁₋₆ alkylamino, N-linked-heterocycloalkyl, and C₃₋₆        cycloalkyl, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and        the alkyl chains of C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆        alkylamino, or di-C₁₋₆ alkylamino are optionally substituted        with one or more substituents independently selected from the        group consisting of fluoro, —CN, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆ alkylamino and        N-linked-heterocycloalkyl.    -   g is 0, 1, or 2; and    -   h is 0, 1, or 2.

In some embodiments of a compound of Formula Ic, g is 0 or 1; R²⁴ ishalogen, —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, or C₁₋₆haloalkoxy; h is 0, 1, or 2; and R²⁵ at each occurrence is independentlyselected from the group consisting of —CN, halogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, alkenyl, C₂₋₆ alkynyl, and C₃₋₆cycloalkyl.

In some embodiments, the compound of Formula Ic has a structure selectedfrom the group consisting of:

-   -   wherein X₁, Y₁, L₂, A₅, A₆, R²², R²³, R²⁴, R²⁵, g and h are as        defined for a compound of Formula Ic. In some embodiments,

wherein

indicates the point of attachment of ring A₆ to L₂, or to ring A₅ whenL₂ is a bond, and wherein U₁ and U₂ are independently CH or N; and R²⁶,R²⁷, R²⁸, R²⁹ and R³⁰ are independently selected from the groupconsisting of hydrogen, —CN, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino, alkylamino,N-linked-heterocycloalkyl, and C₃₋₆ cycloalkyl, wherein C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and the alkyl chains of C₁₋₆ alkoxy, C₁₋₆alkylsulfonyl, C₁₋₆ alkylamino, or di-C₁₋₆ alkylamino are optionallysubstituted with one or more substituents independently selected fromthe group consisting of fluoro, —CN, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆, alkylamino, alkylamino and N-linked-heterocycloalkyl.In some embodiments, g is 0 or 1; R²⁴ is halogen, —CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, or C₁₋₆ haloalkoxy, in some embodiments halogen;and R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ are independently selected from the groupconsisting of hydrogen, —CN, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆cycloalkyl.

In some embodiments, the compound of Formula Ic has a structure selectedfrom the group consisting of:

-   -   wherein L₃ is —NH— or —NH—C(O)—, and X₁, Y₁, A₆, R²², R²³, R²⁵        and h are as defined for a compound of Formula Ic. In some        embodiments,

wherein

indicates the point of attachment of ring A₆ to L₃, or to the indicatedthiophene ring, and wherein U₁ and U₂ are independently CH or N; andR²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ are independently selected from the groupconsisting of hydrogen, —CN, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino, di-C₁₋₆alkylamino, N-linked-heterocycloalkyl, and C₃₋₆ cycloalkyl, wherein C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and the alkyl chains of C₁₋₆ alkoxy,C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino, or di-C₁₋₆ alkylamino areoptionally substituted with one or more substituents independentlyselected from the group consisting of fluoro, —CN, C₃₋₆ cycloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆ alkylamino andN-linked-heterocycloalkyl. In some embodiments, g is 0 or 1; R²⁴ ishalogen, —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, or C₁₋₆haloalkoxy, in some embodiments halogen; and R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰are independently selected from the group consisting of hydrogen, —CN,halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl.

In one embodiment, the compound of Formula I is selected from the groupconsisting of:

-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   9-methyl-9-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-6-thia-8-azaspiro[4.5]dec-7-en-7-amine,-   (S)-9-methyl-9-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-6-thia-8-azaspiro[4.5]dec-7-en-7-amine,-   9-methyl-9-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-(pyrrolidin-1-yl)-6-thia-8-azaspiro[4.5]dec-7-en-7-amine,-   4-(1-(5-bromopyridin-3-yl)-1H-pyrazol-4-yl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   (R)-5-(5-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)thiophen-3-yl)nicotinonitrile,-   4-methyl-4-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-4-methyl-4-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   4-methyl-4-(1-methyl-3-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-5-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-4-(3-chloro-5-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   4-(3-chloro-5-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-5-(5-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-chlorothiophen-2-yl)nicotinonitrile,-   5-(5-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-chlorothiophen-2-yl)nicotinonitrile,-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   2,2-difluoro-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   9,9-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-9,9-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine,-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine,-   N-(3-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   N-(3-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-cyanopicolinamide,-   7-methyl-7-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-4-thia-6-azaspiro[2.5]oct-5-en-5-amine,-   7-methyl-7-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-4-oxa-6-azaspiro[2.5]oct-5-en-5-amine,-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   4′-methyl-4′-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-4′,5′-dihydrospiro[bicyclo[3.1.0]hexane-3,6′-[1,3]thiazin]-2′-amine,-   7-methyl-7-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-4-thia-6-azaspiro[2.5]oct-5-en-5-amine,-   5-(5-(5-amino-7-methyl-4-thia-6-azaspiro[2.5]oct-5-en-7-yl)-4-chlorothiophen-2-yl)nicotinonitrile,-   N-(3-(5-amino-7-methyl-4-thia-6-azaspiro[2.5]oct-5-en-7-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(5-amino-7-methyl-4-oxa-6-azaspiro[2.5]oct-5-en-7-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,8-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-2,5-dioxa-7-azaspiro[3.5]non-6-en-6-amine,-   5-(5-(6-amino-8-methyl-2,5-dioxa-7-azaspiro[3.5]non-6-en-8-yl)thiophen-3-yl)nicotinonitrile,-   8-(4-(5-(cyclopropylethynyl)pyridin-3-yl)thiophen-2-yl)-8-methyl-2,5-dioxa-7-azaspiro[3.5]non-6-en-6-amine,-   8-methyl-8-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-2,5-dioxa-7-azaspiro[3.5]non-6-en-6-amine,-   5-(5-(6-amino-8-methyl-2,5-dioxa-7-azaspiro[3.5]non-6-en-8-yl)-4-chlorothiophen-2-yl)nicotinonitrile,-   N-(3-(6-amino-8-methyl-2,5-dioxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-8-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   5-(5-(6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl)thiophen-3-yl)nicotinonitrile,-   8-(4-(5-(cyclopropylethynyl)pyridin-3-yl)thiophen-2-yl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   8-methyl-8-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   5-(5-(6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-chlorothiophen-2-yl)nicotinonitrile,-   N-(3-(6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   (S)—N-(3-(6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-2,5-dithia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide,-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-8-thia-3-azaspiro[5.5]undec-2-en-2-amine-8,8-dioxide,-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide,-   5-(5-(6-amino-8-methyl-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)thiophen-3-yl)nicotinonitrile,-   8-(4-(5-(cyclopropylethynyl)pyridin-3-yl)thiophen-2-yl)-8-methyl-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide,-   8-methyl-8-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide,-   5-(5-(6-amino-8-methyl-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)-4-chlorothiophen-2-yl)nicotinonitrile,-   N-(3-(6-amino-8-methyl-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)-4-fluorophenyl)-5-fluoropicolinamide,-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dithia-3-azaspiro[5.5]undec-2-en-2-amine-9,9-dioxide,-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-9-thia-3-azaspiro[5.5]undec-2-en-2-amine-9,9-dioxide,-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,8-dithia-3-azaspiro[5.5]undec-2-en-2-amine-8,8-dioxide,-   5-(5-(6-amino-8-methyl-2,5-dithia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)thiophen-3-yl)    nicotinonitrile,-   8-(4-(5-(cyclopropylethynyl)pyridin-3-yl)thiophen-2-yl)-8-methyl-2,5-dithia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide,-   8-methyl-8-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-2,5-dithia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide,-   5-(5-(6-amino-8-methyl-2,5-dithia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)-4-chlorothiophen-2-yl)nicotinonitrile,-   N-(3-(6-amino-8-methyl-2,5-dithia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)-4-fluorophenyl)-5-fluoropicolinamide,-   1-(6-amino-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-thia-7-azaspiro[3.5]non-6-en-2-yl)ethanone,-   1-(6-amino-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-oxa-7-azaspiro[3.5]non-6-en-2-yl)ethanone,-   N-(3-(2-acetyl-6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-acetyl-6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(6-amino-2,2-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(6-amino-2,2-difluoro-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-amino-9,9-difluoro-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   2,2-difluoro-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   9,9-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   2,2,9,9-tetrafluoro-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   5,5,9,9-tetrafluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   9,9-difluoro-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   10,10-difluoro-9-methyl-9-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-6-thia-8-azaspiro[4.5]dec-7-en-7-amine,-   5,5-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   5,5-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   N-(3-(6-amino-2,2,9,9-tetrafluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-amino-5,5,9,9-tetrafluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(7-amino-10,10-difluoro-9-methyl-6-oxa-8-azaspiro[4.5]dec-7-en-9-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-amino-5,5-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   (R)—N-(3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   (S)—N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzamide,-   3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzamide,-   3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzamide,-   3-(6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-cyanopicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloro-3-fluoropicolinamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-(trifluoromethyl)picolinamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloro-3-fluoropicolinamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)cyclopropanecarboxamide,-   (S)—N-(3-(5-amino-7-methyl-4-oxa-6-azaspiro[2.5]oct-5-en-7-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S,E)-8-(2-fluoro-5-(4-fluorostyryl)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide,-   (S,E)-9,9-difluoro-4-(2-fluoro-5-(4-fluorostyryl)phenyl)-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S,E)-8-(5-(4-chlorostyryl)-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)-8-(2-fluoro-5-(5-(prop-1-ynyl)pyridin-3-yl)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-bromopicolinamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-cyclopropylpicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-2-methyloxazole-4-carboxamide,-   N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-4-chloro-2-methoxybenzamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-4-chlorobenzamide,-   N-(3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloropicolinamide,-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-cyanopicolinamide,-   5,5-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (R)—N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-cyanopicolinamide,-   (S)-8-(2-fluoro-5-((5-fluoropyridin-2-yl)methylamino)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide,-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-2-methyloxazole-4-carboxamide,-   N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-cyanopicolinamide,-   (S)-4-methyl-4-(5-methyl-4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   4-(2-fluoro-5-(1-propyl-1H-pyrazol-4-yl)phenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   4-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-8-(5-(7-chloroquinazolin-4-ylamino)-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)—N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide,-   (S)-4-(2-fluoro-5-(3-methoxypyridin-2-ylamino)phenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,    and-   any pharmaceutically acceptable salt thereof.

In one embodiment, the compound of Formula I is selected from the groupconsisting of:

-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   9,9-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-9,9-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine,-   N-(3-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)—N-(3-(6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   (R)—N-(3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   (S)—N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-cyanopicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloro-3-fluoropicolinamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-(trifluoromethyl)picolinamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloro-3-fluoropicolinamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)cyclopropanecarboxamide,-   (S)—N-(3-(5-amino-7-methyl-4-oxa-6-azaspiro[2.5]oct-5-en-7-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S,E)-8-(2-fluoro-5-(4-fluorostyryl)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide,-   (S,E)-9,9-difluoro-4-(2-fluoro-5-(4-fluorostyryl)phenyl)-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S,E)-8-(5-(4-chlorostyryl)-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)-8-(2-fluoro-5-(5-(prop-1-ynyl)pyridin-3-yl)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-bromopicolinamide,-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-cyclopropylpicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-2-methyloxazole-4-carboxamide,-   N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-4-chloro-2-methoxybenzamide,-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-4-chlorobenzamide,-   N-(3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide,-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloropicolinamide,-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-cyanopicolinamide,-   5,5-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (R)—N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-cyanopicolinamide,-   (S)-8-(2-fluoro-5-((5-fluoropyridin-2-yl)methylamino)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide,-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-2-methyloxazole-4-carboxamide,-   N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-cyanopicolinamide,-   (S)-4-methyl-4-(5-methyl-4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   4-(2-fluoro-5-(1-propyl-1H-pyrazol-4-yl)phenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   4-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-8-(5-(7-chloroquinazolin-4-ylamino)-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)—N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide,-   (S)-4-(2-fluoro-5-(3-methoxypyridin-2-ylamino)phenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,    and-   any pharmaceutically acceptable salt thereof.

In one aspect, compounds are provided for use in making a compound ofFormula I, having a structure according to Formula II:

wherein:

-   -   R³¹ is hydrogen or a nitrogen protecting group;    -   R³² is halogen or NH₂; and    -   A₁, A₂, Y, R¹, R², R³, R⁴, R⁵, m, and n are as defined for a        compound of Formula I.

In some embodiments of a compound of Formula II, Y is O. In someembodiments, Y is S.

In some embodiments of a compound of Formula II, A₁ is a C₃₋₁₀carbocyclic ring. In some embodiments A₁ is a C₃₋₆ monocycliccarbocyclic ring. In some embodiments, A₁ is cyclohexane. In someembodiments, A₁ is cyclopentane. In some embodiments, A₁ is cyclobutane.In some embodiments, A₁ is cyclopropane.

In some embodiments of a compound of Formula II, A₁ is a 3 to 10membered heterocyclic ring. In some embodiments A₁ is a 4 to 6 memberedmonocyclic heterocyclic ring. In some embodiments A₁ is a 4 to 6membered monocyclic heterocyclic ring that contains one oxygen atom orone sulfur atom as the only heteroatom. In some embodiments A₁ is a 4 to6 membered monocyclic heterocyclic ring that contains one oxygen atom.In some embodiments A₁ is tetrahydropyran. In some embodiments A₁ istetrahydrofuran. In some embodiments A₁ is oxetane.

In some embodiments of a compound of Formula II, A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring. In some embodiments A₂ isphenyl or a monocyclic 5 membered heteroaryl ring. In some embodimentsA₂ is phenyl or thiophenyl. In some embodiments A₂ is a monocyclic 5membered heteroaryl ring. In some embodiments A₂ is thiophenyl. In someembodiments A₂ is pyrazolyl. In some embodiments, A₂ is phenyl.

In some embodiments of a compound of Formula II, R¹ is hydrogen or C₁₋₃alkyl. In some embodiments R¹ is methyl. In some embodiments, R¹ ishydrogen. In some embodiments, R¹ is ethyl. In some embodiments, R¹ isn-propyl. In some embodiments, R¹ is isopropyl.

In some embodiments of a compound of Formula II, R² and R³ areindependently hydrogen or halogen. In some embodiments, R² and R³ areindependently hydrogen or fluoro. In some embodiments, R² and R³ areboth hydrogen or both fluoro. In some embodiments, R² and R³ are bothhydrogen. In some embodiments, R² and R³ are both halogen. In someembodiments, R² and R³ are both fluoro.

In some embodiments of a compound of Formula II, R⁴ is halogen. In someembodiments, R⁴ is fluoro. In some embodiments, R⁴ is fluoro and m is 1or 2. In some embodiments, R⁴ is fluoro and m is 2. In some embodiments,R⁴ is fluoro, m is 2, and both fluoro are attached to the same carbonatom. In some embodiments, m is 0. In some embodiments, R⁴ is —C(O)CH₃.In some embodiments, R⁴ is —C(O)CH₃ and m is 1.

In some embodiments of a compound of Formula II, R³² is halogen. In someembodiments R³² is NH₂.

In some embodiments of a compound of Formula II, Y is O or S; A₁ is aC₃₋₁₀ carbocyclic ring, in some embodiments a C₃₋₆ monocycliccarbocyclic ring or A₁ is a 3 to 10 membered heterocyclic ring, in someembodiments a 4 to 6 membered monocyclic heterocyclic ring, in someembodiments the 4 to 6 membered monocyclic heterocyclic ring containsone oxygen atom or one sulfur atom as the only heteroatom; A₂ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula II, Y is O or S; A₁ is aC₃₋₁₀ carbocyclic ring, in some embodiments a C₃₋₆ monocycliccarbocyclic ring; A₂ is phenyl, or a monocyclic 5-6 membered heteroarylring, in some embodiments a monocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula II, Y is O or S; A₁ is a 3to 10 membered heterocyclic ring, in some embodiments a 4 to 6 memberedmonocyclic heterocyclic ring, in some embodiments the 4 to 6 memberedmonocyclic heterocyclic ring contains one oxygen atom or one sulfur atomas the only heteroatom; A₂ is phenyl, or a monocyclic 5-6 memberedheteroaryl ring, in some embodiments a monocyclic 5 membered heteroarylring.

In some embodiments of a compound of Formula II, Y is O or S; A₁ is aC₃₋₁₀ carbocyclic ring, in some embodiments a C₃₋₆ monocycliccarbocyclic ring or A₁ is a 3 to 10 membered heterocyclic ring, in someembodiments a 4 to 6 membered monocyclic heterocyclic ring, in someembodiments the 4 to 6 membered monocyclic heterocyclic ring containsone oxygen atom or one sulfur atom as the only heteroatom, in someembodiments, one oxygen atom as the only heteroatom; and A₂ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments phenylor thiophenyl.

In some embodiments of a compound of Formula II, Y is O or S; A₁ is aC₃₋₁₀ carbocyclic ring, in some embodiments a C₃₋₆ monocycliccarbocyclic ring; and A₂ is phenyl, or a monocyclic 5-6 memberedheteroaryl ring, in some embodiments phenyl or thiophenyl.

In some embodiments of a compound of Formula II, Y is O or S; A₁ is a 3to 10 membered heterocyclic ring, in some embodiments a 4 to 6 memberedmonocyclic heterocyclic ring, in some embodiments the 4 to 6 memberedmonocyclic heterocyclic ring contains one oxygen atom or one sulfur atomas the only heteroatom, in some embodiments oxygen as the onlyheteroatom; and A₂ is phenyl, or a monocyclic 5-6 membered heteroarylring, in some embodiments phenyl or thiophenyl.

In some embodiments of a compound of Formula II, further to any of theabove embodiments, R¹ is methyl.

In some embodiments of a compound of Formula II, the compound has astructure according to Formula IIa:

wherein:

-   -   A₂, Y, R⁵, and n are as defined for a compound of Formula I;    -   q and R²⁰ are as defined for a compound of Formula Ia; and    -   R³¹ and R³² are as defended for a compound of Formula II.

In some embodiments of a compound of Formula IIa, Y is O. In someembodiments, Y is S.

In some embodiments of a compound of Formula IIa, q is 0. In someembodiments q is 1.

In some embodiments of a compound of Formula IIa, A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring. In some embodiments A₂ is amonocyclic 5 membered heteroaryl ring. In some embodiments A₂ isthiophenyl. In some embodiments A₂ is pyrazolyl. In some embodiments, A₂is phenyl.

In some embodiments of a compound of Formula IIa, R²⁰ is hydrogen. Insome embodiments, R²⁰ is —OH, ═O, or —OR¹². In some embodiments, R²⁰ is—S(O)_(z)R¹². In some embodiments, R²⁰ is —NR¹³R¹⁴, or ═NR¹⁴. In someembodiments, R²⁰ is —NR¹³R¹⁴.

In some embodiments of a compound of Formula IIa, R³² is halogen. Insome embodiments R³² is NH₂.

In some embodiments of a compound of Formula IIa, Y is O or S; A₂ isphenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments a monocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIa, Y is O or S; q is 0;A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments a monocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIa, Y is O or S; q is 1;A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments a monocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIa, Y is S, and R²⁰ is H.In some embodiments, Y is S; R²⁰ is H; A₂ is phenyl, or a monocyclic 5-6membered heteroaryl ring, in some embodiments a monocyclic 5 memberedheteroaryl ring.

In some embodiments of a compound of Formula IIa, Y is O, and R²⁰ is H.In some embodiments, Y is O; R²⁰ is H; A₂ is phenyl, or a monocyclic 5-6membered heteroaryl ring, in some embodiments a monocyclic 5 memberedheteroaryl ring.

In some embodiments of a compound of Formula IIa, Y is S, q is 0, andR²⁰ is H. In some embodiments, Y is S; q is 0; R²⁰ is H; A₂ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIa, Y is O, q is 0, andR²⁰ is H. In some embodiments, Y is O; q is 0; R²⁰ is H; A₂ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIa, Y is S, q is 1, andR²⁰ is H. In some embodiments, Y is S; q is 1; R²⁰ is H; A₂ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIa, Y is O, q is 1, andR²⁰ is H. In some embodiments, Y is O; q is 1; R²⁰ is H; A₂ is phenyl,or a monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula II, the compound has astructure according to Formula IIb:

wherein:

-   -   A₂, Y, R⁵, and n are as defined for a compound of Formula I;    -   X, r and s are as defined for a compound of Formula Ib; and    -   R³¹ and R³² are as definded for a compound of Formula II.

In some embodiments of a compound of Formula IIb, Y is O. In someembodiments, Y is S.

In some embodiments of a compound of Formula IIb, X is O. In someembodiments, X is S(O)₂.

In some embodiments of a compound of Formula IIb, r and s are both 0. Insome embodiments, r and s are both 1. In some embodiments, one of r ands is 0 and the other is 1.

In some embodiments of a compound of Formula IIb, A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring. In some embodiments A₂ is amonocyclic 5 membered heteroaryl ring. In some embodiments A₂ isthiophenyl. In some embodiments A₂ is pyrazolyl. In some embodiments, A₂is phenyl.

In some embodiments of a compound of Formula IIb, R³² is halogen. Insome embodiments of a compound of Formula IIb, R³² is NH₂.

In some embodiments of a compound of Formula IIb, Y is O or S; A₂ isphenyl, or a monocyclic 5-6 membered heteroaryl ring, in someembodiments a monocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIb, Y is O or S; either rand s are both 0 or r and s are both 1; A₂ is phenyl, or a monocyclic5-6 membered heteroaryl ring, in some embodiments a monocyclic 5membered heteroaryl ring.

In some embodiments of a compound of Formula IIb, Y is O or S; r and sare both 0; A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring,in some embodiments a monocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIb, Y is O or S; r and sare both 1; A₂ is phenyl, or a monocyclic 5-6 membered heteroaryl ring,in some embodiments a monocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIb, Y is O and either rand s are both 0 or r and s are both 1. In some embodiments Y is O;either r and s are both 0 or r and s are both 1; A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIb, Y is S and either rand s are both 0 or r and s are both 1. In some embodiments Y is S;either r and s are both 0 or r and s are both 1; A₂ is phenyl, or amonocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIb, Y is O and r and s areboth 0. In some embodiments Y is O; r and s are both 0; A₂ is phenyl, ora monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIb, Y is S and r and s areboth 1. In some embodiments Y is S; r and s are both 1; A₂ is phenyl, ora monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIb, Y is O and r and s areboth 1. In some embodiments Y is O; r and s are both 1; A₂ is phenyl, ora monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIb, Y is S and r and s areboth 0. In some embodiments Y is S; r and s are both 0; A₂ is phenyl, ora monocyclic 5-6 membered heteroaryl ring, in some embodiments amonocyclic 5 membered heteroaryl ring.

In some embodiments of a compound of Formula IIb, further to any of theabove embodiments of Formula IIb, X is O.

In some embodiments of a compound of Formula IIb, further to any of theabove embodiments of Formula IIb, X is S(O)₂.

In some embodiments of a compound of Formula II, Formula IIa or FormulaIIb, further to any of the above embodiments, A₂ is phenyl, thiophenylor pyrazolyl. In some embodiments, A₂ is phenyl. In some embodiments, A₂is thiophenyl. In some embodiments, A₂ is pyrazolyl.

In some embodiments of a compound of Formula II, Formula IIa or FormulaIIb, further to any of the above embodiments, m is 0 or 1; R⁴ is fluoro,═O, —OR¹², —S(O)_(z)R¹², —C(O)R¹², or —NR¹³R¹⁴, or R²⁰ is —OR¹²,—S(O)_(z)R¹², or —NR¹³R¹⁴; n is 0 or 1; and R⁵ is halogen, —CN, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, or C₁₋₆ haloalkoxy.

In some embodiments of a compound of Formula II, Formula IIa or FormulaIIb, further to any of the above embodiments, R³¹ is hydrogen or anitrogen protecting group, and the nitrogen protecting group is Boc. Insome embodiments, R³¹ is hydrogen. In some embodiments, R³¹ is anitrogen protecting group. In some embodiments, R³¹ is Boc.

In some embodiments of a compound of Formula II, Formula IIa or FormulaIIb, further to any of the above embodiments, Y is O. In someembodiment, further to any of the above embodiments, Y is S.

In some embodiments of a compound of Formula II, Formula IIa or FormulaIIb, further to any of the above embodiments, n is 0, 1 or 2, and eachR⁵ is independently selected from the group consisting of —CN, halogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, N-linked-heterocycloalkyl, and C₃₋₆cycloalkyl, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and thealkyl chains of C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylamino, ordi-C₁₋₆ alkylamino are optionally substituted with one or moresubstituents independently selected from the group consisting of fluoro,—CN, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,alkylamino and N-linked-heterocycloalkyl. In some embodiments, n is 0 or1; and R⁵ is selected from the group consisting of halogen, —CN, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. In someembodiments, further to any of the above embodiments, n is 1 and R⁵ ishalogen.

In some embodiments of a compound of Formula II, the compound has astructure according to Formula IIc:

wherein:

R³³ is hydrogen or Boc;

R³⁴ is halogen or NH₂;

Y₁, X₁, e, f, g, A₅, R²², R²³, and R²⁴ are as defined for a compound ofFormula Ic.

In some embodiments of a compound of Formula IIc, g is 0 or 1; and R²⁴is halogen, —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, or C₁₋₆haloalkoxy.

In some embodiments, the compound of Formula IIc has a structureselected from the group consisting of:

wherein X₁, Y₁, A₅, R²², R²³, R²⁴, and g are as defined for a compoundof Formula Ic and R³³ and R³⁴ are as defined for a compound of FormulaIIc.

In some embodiments, the compound of Formula IIc has a structureselected from the group consisting of:

wherein X₁, Y₁, R²², and R²³, are as defined for a compound of FormulaIc and R³³ and R³⁴ are as defined for a compound of Formula IIC.

In one embodiment, the compound of Formula II is selected from the groupconsisting of:

-   4-(4-bromothiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-4-(4-bromothiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (R)-4-(4-bromothiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   8-(4-bromothiophen-2-yl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   (R)-4-(5-amino-2-fluorophenyl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   4-(5-bromo-2-fluorophenyl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-4-(5-bromo-2-fluorophenyl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-8-(5-bromo-2-fluorophenyl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   (S)-8-(5-amino-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine-   8-(4-bromothiophen-2-yl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)-4-(4-bromo-5-methylthiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   4-(4-bromothiophen-2-yl)-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-4-(4-bromothiophen-2-yl)-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine,-   8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)-8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (R)-8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)-4-(5-bromo-2-fluorophenyl)-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (R)-8-(5-bromo-2-fluorophenyl)-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   (S)-8-(5-bromo-2-fluorophenyl)-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-6-amine,-   (4S)-4-(3-bromothiophen-2-yl)-7,7,8,8,9,9,10,10,11-nonadeutero-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   4-(5-bromo-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-4-(5-bromo-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   (R)-4-(5-bromo-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   4-(4-bromothiophen-2-yl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-7-(5-bromo-2-fluorophenyl)-7-methyl-4-oxa-6-azaspiro[2.5]oct-5-en-5-amine,-   4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   4-(4-bromothiophen-2-yl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (S)-4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   (R)-4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine,-   8-(5-bromo-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (S)-8-(5-bromo-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   (R)-8-(5-bromo-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine,-   tert-butyl    4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (S)-tert-butyl    4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   tert-butyl    4-(5-amino-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (S)-tert-butyl    4-(5-amino-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (S)-tert-butyl    4-(5-bromo-2-fluorophenyl)-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (S)-tert-butyl    4-(5-amino-2-fluorophenyl)-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   tert-butyl    8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (S)-tert-butyl    8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (R)-tert-butyl    8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   tert-butyl    8-(5-amino-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (S)-tert-butyl    8-(5-amino-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (R)-tert-butyl    8-(5-amino-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   tert-butyl    4-(5-bromo-2-fluorophenyl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   tert-butyl    4-(5-amino-2-fluorophenyl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (S)-tert-butyl    8-(5-bromo-2-fluorophenyl)-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (R)-tert-butyl    8-(5-bromo-2-fluorophenyl)-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (S)-tert-butyl    8-(5-amino-2-fluorophenyl)-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (R)-tert-butyl    8-(5-amino-2-fluorophenyl)-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (S)-tert-butyl    8-(5-bromo-2-fluorophenyl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (S)-tert-butyl    8-(5-amino-2-fluorophenyl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   tert-butyl    4-(5-bromo-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (S)-tert-butyl    4-(5-bromo-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (R)-tert-butyl    4-(5-bromo-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   tert-butyl    4-(5-amino-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (S)-tert-butyl    4-(5-amino-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (R)-tert-butyl    4-(5-amino-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (S)-tert-butyl    7-(5-bromo-2-fluorophenyl)-7-methyl-4-oxa-6-azaspiro[2.5]oct-5-en-5-ylcarbamate,-   (S)-tert-butyl    7-(5-amino-2-fluorophenyl)-7-methyl-4-oxa-6-azaspiro[2.5]oct-5-en-5-ylcarbamate,-   tert-butyl    4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (R)-tert-butyl    4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (S)-tert-butyl    4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   tert-butyl    4-(5-amino-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (R)-tert-butyl    4-(5-amino-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   (S)-tert-butyl    4-(5-amino-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate,-   tert-butyl    8-(5-bromo-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (R)-tert-butyl    8-(5-bromo-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (S)-tert-butyl    8-(5-bromo-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   tert-butyl    8-(5-amino-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate,-   (R)-tert-butyl    8-(5-amino-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate,    and-   (S)-tert-butyl    8-(5-amino-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate.

In one aspect, compounds are provided for use in making a compound ofFormula I, having a structure according to Formula III, wherein FormulaIII is selected from the group consisting of:

wherein:

-   -   R³⁵ is halogen;    -   R³⁶ is OH, OR³⁹, SH, or SR⁴⁰;    -   R³⁷ is OH, SH, or SR⁴⁰;    -   R³⁸ is hydrogen or

wherein

indicates the attachment point to NH;

-   -   R³⁹ is an oxygen protecting group;    -   R⁴⁰ is a thiol protecting group; and    -   A₁, A₂, R¹, R², R³, R⁴, R⁵, m, and n are as defined for a        compound of Formula I.

In some embodiments of a compound of Formula III, the compound has astructure selected from the group consisting of:

wherein:

-   -   R⁴¹ is OH, TBDMS protected O, SH, or p-methoxybenzyl protected        S;    -   R⁴² is OH, SH, or p-methoxybenzyl protected S;    -   R⁴³ is hydrogen or

wherein

indicates the attachment point to NH;

-   -   X₁, e, f, g, A₅, R²², R²³, and R²⁴ are as defined for compounds        of Formula Ic.

In some embodiments of a compound of Formula III selected from IIIe,IIIf, IIIg and IIIh, g is 0 or 1; and R²⁴ is halogen, —CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, or C₁₋₆ haloalkoxy.

In some embodiments of a compound of Formula III,

is selected from the group consisting of:

In one embodiment, a compound as described herein, e.g. a compound ofFormula I, is an inhibitor of BACE1 and/or BACE2 protease activity, withan IC₅₀ of less than about 1.0 μM, less than about 0.9 μM, less thanabout 0.8 μM less than about 0.7 μM, less than about 0.6 μM, less thanabout 0.5 less than about 0.4 μM, less than about 0.3 μM, or less thanabout 0.2 μM in a BACE1 and/or BACE2 protease activity assay. In oneembodiment, a compound of Formula I has an IC₅₀ of less than about 100nM, less than about 90 nM, less than about 80 nM, less than about 70 nM,less than about 60 nM, less than about 50 nM, less than about 40 nM,less than about 30 nM, less than about 20 nM or less than about 10 nM ina BACE1 and/or BACE2 protease activity assay.

In one embodiment, a compound as described herein, e.g. a compound ofFormula I, is an inhibitor of BACE1 protease activity, with an IC₅₀ ofless than about 1.0 μM, less than about 0.9 μM, less than about 0.8 μM,less than about 0.7 μM, less than about 0.6 μM, less than about 0.5 μM,less than about 0.4 μM, less than about 0.3 or less than about 0.2 μM ina BACE1 protease activity assay. In one embodiment, a compound ofFormula I has an IC₅₀ of less than about 100 nM, less than about 90 nM,less than about 80 nM, less than about 70 nM, less than about 60 nM,less than about 50 nM, less than about 40 nM, less than about 30 nM,less than about 20 nM or less than about 10 nM in a BACE1 proteaseactivity assay.

In one embodiment, a compound as described herein, e.g. a compound ofFormula I, is an inhibitor of BACE2 protease activity, with an IC₅₀ ofless than about 1.0 μM, less than about 0.9 μM, less than about 0.8 μM,less than about 0.7 less than about 0.6 μM, less than about 0.5 lessthan about 0.4 μM, less than about 0.3 μM, or less than about 0.2 μM ina BACE2 protease activity assay. In one embodiment, a compound ofFormula I has an IC₅₀ of less than about 100 nM, less than about 90 nM,less than about 80 nM, less than about 70 nM, less than about 60 nM,less than about 50 nM, less than about 40 nM, less than about 30 nM,less than about 20 nM or less than about 10 nM in a BACE2 proteaseactivity assay.

In one embodiment, a compound as described herein, e.g. a compound ofFormula I, is an inhibitor of BACE1 protease activity, and is selectivecompared to the activity of one or more other proteases, including, butnot limited to, one or more of Cathepsin D protease activity, CathepsinE protease activity, Renin protease activity, HIV protease activity,Pepsin protease activity, and/or BACE2 protease activity. In someinstances, a compound of Formula I is an inhibitor of BACE1 proteaseactivity, and is selective compared to Cathepsin D protease activity. Insome instances, a compound of Formula I is an inhibitor of BACE1protease activity, and is selective compared to Cathepsin E proteaseactivity. In some instances, a compound of Formula I is an inhibitor ofBACE1 protease activity, and is selective compared to Renin proteaseactivity. In some instances, a compound of Formula I is an inhibitor ofBACE1 protease activity, and is selective compared to HIV proteaseactivity. In some instances, a compound of Formula I is an inhibitor ofBACE1 protease activity, and is selective compared to Pepsin proteaseactivity. In some instances, a compound of Formula I is an inhibitor ofBACE1 protease activity, and is selective compared to BACE2 proteaseactivity. In some instances, a compound of Formula I is an inhibitor ofBACE1 protease activity, and is selective compared to Cathepsin Dprotease activity and BACE2 protease activity. For the purpose of thisapplication the selectivity of the instant compounds for BACE1 overanother protease, such as Cathepsin D or BACE2 is expressed as a ratioof IC₅₀ values for a suitable activity assay or in some instances as aratio of % inhibition at a given concentration of compound, such as at10 μM. These values can be determined using assays known in the art orthose described herein (see e.g., Example A).

In one embodiment, a compound as described herein, e.g. a compound ofFormula I, is characterized by the following inhibitory activitiesinvolving BACE1 protease activity. In one embodiment, the ratio ofIC₅₀(BACE1)÷IC₅₀(Cathepsin D) is less than about 1, less than about 0.9,less than about 0.8, less than about 0.7, less than about 0.6, less thanabout 0.5, less than about 0.4, less than about 0.3, less than about 0.2or less than about 0.1. In one embodiment, the ratio ofIC₅₀(BACE1)÷IC₅₀(Cathepsin D) is less than about 0.09, less than about0.08, less than about 0.07, less than about 0.06, less than about 0.05,less than about 0.04, less than about 0.03, less than about 0.02 or lessthan about 0.01. In one embodiment, the ratio ofIC₅₀(BACE1)÷IC₅₀(Cathepsin D) is less than about 0.009, less than about0.008, less than about 0.007, less than about 0.006, less than about0.005, less than about 0.004, less than about 0.003, less than about0.002 or less than about 0.001. In one embodiment, the ratio ofIC₅₀(BACE1)÷IC₅₀(Cathepsin D) is less than about 0.0009, less than about0.0008, less than about 0.0007, less than about 0.0006, less than about0.0005, less than about 0.0004, less than about 0.0003, less than about0.0002 or less than about 0.0001.

In one embodiment, a compound as described herein, e.g. a compound ofFormula 1, is characterized by the following inhibitory activitiesinvolving BACE1 protease activity. In one embodiment, the ratio ofIC₅₀(BACE1)÷IC₅₀(BACE2) is less than about 1, less than about 0.9, lessthan about 0.8, less than about 0.7, less than about 0.6, less thanabout 0.5, less than about 0.4, less than about 0.3, less than about 0.2or less than about 0.1. In one embodiment, the ratio of IC₅₀(BACE1)IC₅₀(BACE2) is less than about 0.09, less than about 0.08, less thanabout 0.07, less than about 0.06, less than about 0.05, less than about0.04, less than about 0.03, less than about 0.02 or less than about0.01. In one embodiment, the ratio of IC₅₀(BACE1)÷IC₅₀(BACE2) is lessthan about 0.009, less than about 0.008, less than about 0.007, lessthan about 0.006, less than about 0.005, less than about 0.004, lessthan about 0.003, less than about 0.002 or less than about 0.001. In oneembodiment, the ratio of IC₅₀(BACE1)÷IC₅₀(BACE2) is less than about0.0009, less than about 0.0008, less than about 0.0007, less than about0.0006, less than about 0.0005, less than about 0.0004, less than about0.0003, less than about 0.0002 or less than about 0.0001.

In one aspect, any tautomer, stereoisomer, prodrug, derivative,conjugate, polymorph, isotopically enhanced form, pharmaceuticallyacceptable salt or pharmaceutically acceptable solvate of a compound ofFormula I is provided. In one embodiment, any tautomer of a compound ofFormula I is provided. In one embodiment, any stereoisomer of a compoundof Formula I is provided. In one embodiment, any prodrug of a compoundof Formula I is provided. In one embodiment, any derivative of acompound of Formula I is provided. In one embodiment, any conjugate of acompound of Formula I is provided. In one embodiment, any polymorph of acompound of Formula I is provided. In one embodiment, any isotopicallyenhanced form of a compound of Formula I is provided. In one embodiment,any pharmaceutically acceptable salt of a compound of Formula I isprovided. In one embodiment, any polymorph of any pharmaceuticallyacceptable salt of a compound of Formula I is provided. In oneembodiment, any pharmaceutically acceptable solvate of a compound ofFormula I is provided. In one embodiment, any polymorph of anypharmaceutically acceptable solvate of a compound of Formula I isprovided.

In one aspect, a pharmaceutical composition comprising a compound asdescribed herein, e.g. a compound of Formula I, and a pharmaceuticallyacceptable carrier is provided. In one embodiment, a pharmaceuticalcomposition comprising any tautomer of a compound of Formula I and apharmaceutically acceptable carrier is provided. In one embodiment, apharmaceutical composition comprising any stereoisomer of a compound ofFormula I and a pharmaceutically acceptable carrier is provided. In oneembodiment, a pharmaceutical composition comprising any prodrug of acompound of Formula I and a pharmaceutically acceptable carrier isprovided. In one embodiment, a pharmaceutical composition comprising anyderivative of a compound of Formula I and a pharmaceutically acceptablecarrier is provided. In one embodiment, a pharmaceutical compositioncomprising any conjugate of a compound of Formula I and apharmaceutically acceptable carrier is provided. In one embodiment, apharmaceutical composition comprising any polymorph of a compound ofFormula I and a pharmaceutically acceptable carrier is provided. In oneembodiment, a pharmaceutical composition comprising any isotopicallyenhanced form of a compound of Formula I and a pharmaceuticallyacceptable carrier is provided. In one embodiment, a pharmaceuticalcomposition comprising any pharmaceutically acceptable salt of acompound of Formula I and a pharmaceutically acceptable carrier isprovided. In one embodiment, a pharmaceutical composition comprising anypolymorph of any pharmaceutically acceptable salt of a compound ofFormula I and a pharmaceutically acceptable carrier is provided. In oneembodiment, a pharmaceutical composition comprising any pharmaceuticallyacceptable solvate of a compound of Formula I and a pharmaceuticallyacceptable carrier is provided. In one embodiment, a pharmaceuticalcomposition comprising any polymorph of any pharmaceutically acceptablesolvate of a compound of Formula I and a pharmaceutically acceptablecarrier is provided.

In one aspect, a kit is provided that includes a compound or compositionthereof as described herein, e.g. a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, or a compositioncomprising such a compound or pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the kit includes a a compound ofFormula I, or a pharmaceutically acceptable salt thereof, or acomposition comprising such a compound or pharmaceutically acceptablesalt thereof. In some embodiments, the compound or composition thereofis packaged, e.g., in a vial, bottle or similar container, which may befurther packaged, e.g., within a box, envelope, or similar container. Insome embodiments, the compound or composition thereof is approved by theU.S. Food and Drug Administration or similar regulatory agency foradministration to a mammal, e.g., a human. In some embodiments thecompound or composition thereof is approved for administration to amammal, e.g., a human, for a BACE mediated disease or condition,including a BACE1 and/or BACE2 mediated condition. In one embodiment,such a kit includes written instructions for use and/or other indicationthat the compound or composition is suitable or approved foradministration to a mammal, e.g., a human, for a suitable disease orcondition. In some embodiments, the compound or composition is packagedin unit dose or single dose form, e.g., single dose pills, capsules, orthe like.

In one aspect, a compound of Formula I, or a pharmaceutically acceptablesalt or solvate thereof, or a composition comprising such a compound orpharmaceutically acceptable salt or solvate thereof, is useful in thetreatment and/or prevention of a BACE mediated disorder, or an Aβpeptide related disorder. In some embodiments, a compound of Formula I,or a pharmaceutically acceptable salt thereof, or a compositioncomprising such a compound or pharmaceutically acceptable salt thereof,is useful in the treatment and/or prevention of a BACE mediateddisorder, or an Aβ peptide related disorder. In one embodiment, use of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof, or a composition comprising such a compound or pharmaceuticallyacceptable salt or solvate thereof, for the treatment of a disease isprovided; in some embodiments the use of a compound of Formula I, or apharmaceutically acceptable salt thereof, or a composition comprisingsuch a compound or pharmaceutically acceptable salt thereof, for thetreatment of a disease is provided; wherein the disease is selected fromthe group consisting of neurological diseases, such as Alzheimer'sdisease (including any disorders associated with Alzheimer's disease,such as dementia, attention deficit, depression, agitation, mildcognitive impairment, cognitive decline, memory loss, senility,neurodegeneration, olfactory impairment), diffuse Lewy body typeAlzheimer's disease, Parkinson's disease (including dementia associatedwith Parkinson's disease), frontotemporal dementias with parkinsonism,progressive supranuclear palsy (including dementia associated withsupranuclear palsy), cortical basal degeneration (including dementiaassociated with cortical basal degeneration), dementia with Lewy bodies,presenile dementia, senile dementia, multi-infarct dementia, dementia ofmixed vascular and degenerative origin, mild cognitive impairment, Downsyndrome (including dementia and cognitive impairment associated withDown syndrome), hereditary cerebral hemorrhage with amyloidosis of theDutch-Type, cerebral amyloid angiopathy, amyotrophic lateral sclerosis,Huntington's disease, and demyelinating diseases (including multiplesclerosis, idiopathic inflammatory demyelinating disease, chronicinflammatory demyelinating polyneuropathy, Guillain-Barre syndrome,progressive multifocal leukoencephalopathy, and Charcot-Marie-ToothDisease); other CNS disorders, such as traumatic brain injury, braininflammation, spinal cord injury, and nerve injury; anxiety disorders(including obsessive-compulsive disorder, general anxiety disorder andpost-traumatic disorder); ocular diseases including glaucoma andage-related macular degeneration; cardiovascular diseases such asmyocardial infarction, arterial thrombosis, transient ischemic attack,and stroke (including dementia associated with stroke andneurodegeneration associated with stroke); other amyloidoses, such asfamilial amyloidotic polyneuropathy, hemodialysis associated amyloidosis(accumulation of β2-microglobulins and complications arising therefrom);prion diseases such as Creutzfeldt-Jakob disease,Gerstmann-Stráussler-Scheinker syndrome, scrapie (including Kuru scrapieand animal scrapie), and bovine spongiform encephalitis; cancers, suchas glioblastoma multiforme, multiple myeloma, malignant melanoma, Kaposisarcoma, and breast cancer; autoimmune diseases such as rheumatoidarthritis, Sjogren syndrome, lupus erythematosus, and Graves disease;inflammatory diseases such as inclusion body myositis, dermatomyositis,macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatousarthritis, and inflammatory reactions; and other diseases, includingnarcolepsy, type 2 diabetes, hypertension, Wilson's disease, Whipple'sdisease, spinocerebellar ataxia 1, spinocerebellar ataxia 7, andKostmann disease.

In one embodiment, use of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, or a composition comprising such acompound or pharmaceutically acceptable salt or solvate thereof, for thetreatment of a disease is provided; in some embodiments the use of acompound of Formula I, or a pharmaceutically acceptable salt thereof, ora composition comprising such a compound or pharmaceutically acceptablesalt thereof, for the treatment of a disease is provided; wherein thedisease is selected from the group consisting of Alzheimer's disease,diffuse Lewy body type Alzheimer's disease, Parkinson's disease,frontotemporal dementias with parkinsonism, progressive supranuclearpalsy, cortical basal degeneration, dementia with Lewy bodies, preseniledementia, senile dementia, multi-infarct dementia, dementia of mixedvascular and degenerative origin, mild cognitive impairment, Downsyndrome, cerebral amyloid angiopathy, amyotrophic lateral sclerosis,multiple sclerosis, traumatic brain injury, brain inflammation, spinalcord injury, nerve injury, glaucoma, age-related macular degeneration,myocardial infarction, arterial thrombosis, transient ischemic attack,and stroke. In one embodiment, the disease is selected from the groupconsisting of Alzheimer's disease, Down syndrome, amyotrophic lateralsclerosis, multiple sclerosis, traumatic brain injury, spinal cordinjury, nerve injury, glaucoma, age-related macular degeneration,myocardial infarction, transient ischemic attack, and stroke. In oneembodiment, the disease is Alzheimer's disease.

In one embodiment, use of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, or a composition comprising such acompound or pharmaceutically acceptable salt or solvate thereof, in thepreparation of a medicament for the treatment of a disease is provided;in some embodiments the use of a compound of Formula I, or apharmaceutically acceptable salt thereof, or a composition comprisingsuch a compound or pharmaceutically acceptable salt thereof, in thepreparation of a medicament for the treatment of a disease is provided;wherein the disease is selected from the group consisting ofneurological diseases, such as Alzheimer's disease (including anydisorders associated with Alzheimer's disease, such as dementia,attention deficit, depression, agitation, mild cognitive impairment,cognitive decline, memory loss, senility, neurodegeneration, olfactoryimpairment), diffuse Lewy body type Alzheimer's disease, Parkinson'sdisease (including dementia associated with Parkinson's disease),frontotemporal dementias with parkinsonism, progressive supranuclearpalsy (including dementia associated with supranuclear palsy), corticalbasal degeneration (including dementia associated with cortical basaldegeneration), dementia with Lewy bodies, presenile dementia, seniledementia, multi-infarct dementia, dementia of mixed vascular anddegenerative origin, mild cognitive impairment, Down syndrome (includingdementia and cognitive impairment associated with Down syndrome),hereditary cerebral hemorrhage with amyloidosis of the Dutch-Type,cerebral amyloid angiopathy, amyotrophic lateral sclerosis, Huntington'sdisease, and demyelinating diseases (including multiple sclerosis,idiopathic inflammatory demyelinating disease, chronic inflammatorydemyelinating polyneuropathy, Guillain-Barre syndrome, progressivemultifocal leukoencephalopathy, and Charcot-Marie-Tooth Disease); otherCNS disorders, such as traumatic brain injury, brain inflammation,spinal cord injury, and nerve injury; anxiety disorders (includingobsessive-compulsive disorder, general anxiety disorder andpost-traumatic disorder); ocular diseases including glaucoma andage-related macular degeneration; cardiovascular diseases such asmyocardial infarction, arterial thrombosis, transient ischemic attack,and stroke (including dementia associated with stroke andneurodegeneration associated with stroke); other amyloidoses, such asfamilial amyloidotic polyneuropathy, hemodialysis associated amyloidosis(accumulation of β2-microglobulins and complications arising therefrom);prion diseases such as Creutzfeldt-Jakob disease,Gerstmann-Stráussler-Scheinker syndrome, scrapie (including Kuru scrapieand animal scrapie), and bovine spongiform encephalitis; cancers, suchas glioblastoma multiforme, multiple myeloma, malignant melanoma, Kaposisarcoma, and breast cancer; autoimmune diseases such as rheumatoidarthritis, Sjogren syndrome, lupus erythematosus, and Graves disease;inflammatory diseases such as inclusion body myositis, dermatomyositis,macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatousarthritis, and inflammatory reactions; and other diseases, includingnarcolepsy, type 2 diabetes, hypertension, Wilson's disease, Whipple'sdisease, spinocerebellar ataxia 1, spinocerebellar ataxia 7, andKostmann disease.

In one embodiment, use of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, or a composition comprising such acompound or pharmaceutically acceptable salt or solvate thereof, in thepreparation of a medicament for the treatment of a disease is provided;in some embodiments the use of a compound of Formula I, or apharmaceutically acceptable salt thereof, or a composition comprisingsuch a compound or pharmaceutically acceptable salt thereof, in thepreparation of a medicament for the treatment of a disease is provided;wherein the disease is selected from the group consisting of Alzheimer'sdisease, diffuse Lewy body type Alzheimer's disease, Parkinson'sdisease, frontotemporal dementias with parkinsonism, progressivesupranuclear palsy, cortical basal degeneration, dementia with Lewybodies, presenile dementia, senile dementia, multi-infarct dementia,dementia of mixed vascular and degenerative origin, mild cognitiveimpairment, Down syndrome, cerebral amyloid angiopathy, amyotrophiclateral sclerosis, multiple sclerosis, traumatic brain injury, braininflammation, spinal cord injury, nerve injury, glaucoma, age-relatedmacular degeneration, myocardial infarction, arterial thrombosis,transient ischemic attack, and stroke. In one embodiment, the disease isselected from the group consisting of Alzheimer's disease, Downsyndrome, amyotrophic lateral sclerosis, multiple sclerosis, traumaticbrain injury, spinal cord injury, nerve injury, glaucoma, age-relatedmacular degeneration, myocardial infarction, transient ischemic attack,and stroke. In one embodiment, the disease is Alzheimer's disease.

In one aspect, a method is provided for treating a disease. The methodincludes administering to a mammalian subject (e.g., human subject orpatient) in need thereof a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof, or a composition comprising such a compound or pharmaceuticallyacceptable salt or solvate thereof. In one embodiment, the methodincludes administering to a mammalian subject (e.g., human subject orpatient) in need thereof a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof, ora composition comprising such a compound or pharmaceutically acceptablesalt thereof. In one embodiment, a method of treating or preventing aBACE mediated disorder, or Aβ peptide related disorder is providedcomprising administering to a mammalian subject in need thereof atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, or a compositioncomprising such a compound or pharmaceutically acceptable salt orsolvate thereof; in one embodiment the method is provided comprisingadministering to a mammalian subject in need thereof a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, or a composition comprising such a compound orpharmaceutically acceptable salt thereof. In one embodiment, a method oftreating a disease is provided comprising administering to a mammaliansubject in need thereof a therapeutically effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt or solvate thereof,or a composition comprising such a compound or pharmaceuticallyacceptable salt or solvate thereof; in one embodiment the method isprovided comprising administering to a mammalian subject in need thereofa therapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, or a composition comprisingsuch a compound or pharmaceutically acceptable salt thereof; wherein thedisease is selected from the group consisting of neurological diseases,such as Alzheimer's disease (including any disorders associated withAlzheimer's disease, such as dementia, attention deficit, depression,agitation, mild cognitive impairment, cognitive decline, memory loss,senility, neurodegeneration, olfactory impairment), diffuse Lewy bodytype Alzheimer's disease, Parkinson's disease (including dementiaassociated with Parkinson's disease), frontotemporal dementias withparkinsonism, progressive supranuclear palsy (including dementiaassociated with supranuclear palsy), cortical basal degeneration(including dementia associated with cortical basal degeneration),dementia with Lewy bodies, presenile dementia, senile dementia,multi-infarct dementia, dementia of mixed vascular and degenerativeorigin, mild cognitive impairment, Down syndrome (including dementia andcognitive impairment associated with Down syndrome), hereditary cerebralhemorrhage with amyloidosis of the Dutch-Type, cerebral amyloidangiopathy, amyotrophic lateral sclerosis, Huntington's disease, anddemyelinating diseases (including multiple sclerosis, idiopathicinflammatory demyelinating disease, chronic inflammatory demyelinatingpolyneuropathy, Guillain-Barre syndrome, progressive multifocalleukoencephalopathy, and Charcot-Marie-Tooth Disease); other CNSdisorders, such as traumatic brain injury, brain inflammation, spinalcord injury, and nerve injury; anxiety disorders (includingobsessive-compulsive disorder, general anxiety disorder andpost-traumatic disorder); ocular diseases including glaucoma andage-related macular degeneration; cardiovascular diseases such asmyocardial infarction, arterial thrombosis, transient ischemic attack,and stroke (including dementia associated with stroke andneurodegeneration associated with stroke); other amyloidoses, such asfamilial amyloidotic polyneuropathy, hemodialysis associated amyloidosis(accumulation of β2-microglobulins and complications arising therefrom);prion diseases such as Creutzfeldt-Jakob disease,Gerstmann-Stráussler-Scheinker syndrome, scrapie (including Kuru scrapieand animal scrapie), and bovine spongiform encephalitis; cancers, suchas glioblastoma multiforme, multiple myeloma, malignant melanoma, Kaposisarcoma, and breast cancer; autoimmune diseases such as rheumatoidarthritis, Sjogren syndrome, lupus erythematosus, and Graves disease;inflammatory diseases such as inclusion body myositis, dermatomyositis,macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatousarthritis, and inflammatory reactions; and other diseases, includingnarcolepsy, type 2 diabetes, hypertension, Wilson's disease, Whipple'sdisease, spinocerebellar ataxia 1, spinocerebellar ataxia 7, andKostmann disease.

In one embodiment, a method of treating a disease is provided comprisingadministering to a mammalian subject in need thereof a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, or a composition comprising such acompound or pharmaceutically acceptable salt or solvate thereof; in oneembodiment, the method is provided comprising administering to amammalian subject in need thereof a therapeutically effective amount ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,or a composition comprising such a compound or pharmaceuticallyacceptable salt thereof; wherein the disease is selected from the groupconsisting of Alzheimer's disease, diffuse Lewy body type Alzheimer'sdisease, Parkinson's disease, frontotemporal dementias withparkinsonism, progressive supranuclear palsy, cortical basaldegeneration, dementia with Lewy bodies, presenile dementia, seniledementia, multi-infarct dementia, dementia of mixed vascular anddegenerative origin, mild cognitive impairment, Down syndrome, cerebralamyloid angiopathy, amyotrophic lateral sclerosis, multiple sclerosis,traumatic brain injury, brain inflammation, spinal cord injury, nerveinjury, glaucoma, age-related macular degeneration, myocardialinfarction, arterial thrombosis, transient ischemic attack, and stroke.In one embodiment, the disease is selected from the group consisting ofAlzheimer's disease, Down syndrome, amyotrophic lateral sclerosis,multiple sclerosis, traumatic brain injury, spinal cord injury, nerveinjury, glaucoma, age-related macular degeneration, myocardialinfarction, transient ischemic attack, and stroke. In one embodiment,the disease is Alzheimer's disease.

In one embodiment, a method of treating a neurodegenerative disease isprovided comprising administering to a mammalian subject in need thereofa therapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, or a compositioncomprising such a compound or pharmaceutically acceptable salt orsolvate thereof; in one embodiment, the method is provided comprisingadministering to a mammalian subject in need thereof a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, or a composition comprising such a compound orpharmaceutically acceptable salt thereof; wherein the neurodegenerativedisease is selected from the group consisting of Alzheimer's disease(including any disorders associated with Alzheimer's disease, such asdementia, attention deficit, depression, agitation, mild cognitiveimpairment, cognitive decline, memory loss, senility, neurodegeneration,olfactory impairment), diffuse Lewy body type Alzheimer's disease,Parkinson's disease (including dementia associated with Parkinson'sdisease), frontotemporal dementias with parkinsonism, progressivesupranuclear palsy (including dementia associated with supranuclearpalsy), cortical basal degeneration (including dementia associated withcortical basal degeneration), dementia with Lewy bodies, preseniledementia, senile dementia, multi-infarct dementia, dementia of mixedvascular and degenerative origin, mild cognitive impairment, Downsyndrome (including dementia and cognitive impairment associated withDown syndrome), hereditary cerebral hemorrhage with amyloidosis of theDutch-Type, cerebral amyloid angiopathy, amyotrophic lateral sclerosis,Huntington's disease, and demyelinating diseases (including multiplesclerosis, idiopathic inflammatory demyelinating disease, chronicinflammatory demyelinating polyneuropathy, Guillain-Barre syndrome,progressive multifocal leukoencephalopathy, and Charcot-Marie-ToothDisease); and other CNS disorders, such as traumatic brain injury, braininflammation, spinal cord injury, and nerve injury. In one embodiment,the neurodegenerative disease is selected from the group consisting ofAlzheimer's disease, diffuse Lewy body type Alzheimer's disease,Parkinson's disease, frontotemporal dementias with parkinsonism,progressive supranuclear palsy, cortical basal degeneration, dementiawith Lewy bodies, presenile dementia, senile dementia, multi-infarctdementia, dementia of mixed vascular and degenerative origin, mildcognitive impairment, Down syndrome, cerebral amyloid angiopathy,amyotrophic lateral sclerosis, multiple sclerosis, traumatic braininjury, brain inflammation, spinal cord injury, and nerve injury. In oneembodiment, the neurodegenerative disease is selected from the groupconsisting of Alzheimer's disease, Down syndrome, amyotrophic lateralsclerosis, multiple sclerosis, traumatic brain injury, spinal cordinjury, and nerve injury. In one embodiment, the neurodegenerativedisease is Alzheimer's disease.

In one embodiment, a method of treating Alzheimer's disease is providedcomprising administering to a mammalian subject in need thereof atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, or a compositioncomprising such a compound or pharmaceutically acceptable salt orsolvate thereof. In one embodiment, the method of treating Alzheimer'sdisease is provided comprising administering to a mammalian subject inneed thereof a therapeutically effective amount of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, or a compositioncomprising such a compound or pharmaceutically acceptable salt thereof.

In one embodiment, a method of reducing the level of Aβ peptide in thebrain of a mammalian subject is provided comprising administering to themammalian subject in need thereof a therapeutically effective amount ofa compound of Formula I, or a pharmaceutically acceptable salt orsolvate thereof, or a composition comprising such a compound orpharmaceutically acceptable salt or solvate thereof; in one embodimentthe method is provided comprising administering to the mammalian subjectin need thereof a therapeutically effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, or acomposition comprising such a compound or pharmaceutically acceptablesalt thereof. In one embodiment, the method of reducing the level of Aβpeptide in the brain of a mammalian subject provides treatment of adisease selected from the group consisting of Alzheimer's disease,diffuse Lewy body type Alzheimer's disease, Parkinson's disease,frontotemporal dementias with parkinsonism, progressive supranuclearpalsy, cortical basal degeneration, dementia with Lewy bodies, preseniledementia, senile dementia, multi-infarct dementia, dementia of mixedvascular and degenerative origin, mild cognitive impairment, Downsyndrome, cerebral amyloid angiopathy, traumatic brain injury, and braininflammation.

In one embodiment, a method of reducing the level of CTFβ fragment inthe brain of a mammalian subject is provided comprising administering toa mammalian subject in need thereof a therapeutically effective amountof a compound of Formula I, or a pharmaceutically acceptable salt orsolvate thereof, or a composition comprising such a compound orpharmaceutically acceptable salt or solvate thereof; in one embodimentthe method is provided comprising administering to the mammalian subjectin need thereof a therapeutically effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, or acomposition comprising such a compound or pharmaceutically acceptablesalt thereof. In one embodiment, the method of reducing the level ofCTFβ fragment in the brain of a mammalian subject provides treatment ofa disease selected from the group consisting of Alzheimer's disease,diffuse Lewy body type Alzheimer's disease, Parkinson's disease,frontotemporal dementias with parkinsonism, progressive supranuclearpalsy, cortical basal degeneration, dementia with Lewy bodies, preseniledementia, senile dementia, multi-infarct dementia, dementia of mixedvascular and degenerative origin, mild cognitive impairment, Downsyndrome, cerebral amyloid angiopathy, traumatic brain injury, and braininflammation.

In one embodiment, a method of reducing the level of sAPPβ fragment inthe brain of a mammalian subject is provided comprising administering toa mammalian subject in need thereof a therapeutically effective amountof a compound of Formula I, or a pharmaceutically acceptable salt orsolvate thereof, or a composition comprising such a compound orpharmaceutically acceptable salt or solvate thereof; in one embodimentthe method is provided comprising administering to the mammalian subjectin need thereof a therapeutically effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, or acomposition comprising such a compound or pharmaceutically acceptablesalt thereof. In one embodiment, the method of reducing the level ofsAPPβ fragment in the brain of a mammalian subject provides treatment ofa disease selected from the group consisting of Alzheimer's disease,diffuse Lewy body type Alzheimer's disease, Parkinson's disease,frontotemporal dementias with parkinsonism, progressive supranuclearpalsy, cortical basal degeneration, dementia with Lewy bodies, preseniledementia, senile dementia, multi-infarct dementia, dementia of mixedvascular and degenerative origin, mild cognitive impairment, Downsyndrome, cerebral amyloid angiopathy, traumatic brain injury, and braininflammation.

In one embodiment, a method of preventing Aβ peptide aggregation,oligomerization, fibrillization or plaque formation in a mammaliansubject is provided comprising administering to a mammalian subject inneed thereof a therapeutically effective amount of a compound of FormulaI, or a pharmaceutically acceptable salt or solvate thereof, or acomposition comprising such a compound or pharmaceutically acceptablesalt or solvate thereof; in one embodiment the method is providedcomprising administering to the mammalian subject in need thereof atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, or a composition comprisingsuch a compound or pharmaceutically acceptable salt thereof. In oneembodiment, the method of preventing Aβ peptide aggregation,oligomerization, fibrillization or plaque formation in a mammaliansubject provides treatment of a disease selected from the groupconsisting of Alzheimer's disease, diffuse Lewy body type Alzheimer'sdisease, Parkinson's disease, frontotemporal dementias withparkinsonism, progressive supranuclear palsy, cortical basaldegeneration, dementia with Lewy bodies, presenile dementia, seniledementia, multi-infarct dementia, dementia of mixed vascular anddegenerative origin, mild cognitive impairment, Down syndrome, cerebralamyloid angiopathy, traumatic brain injury, and brain inflammation.

In one embodiment, the use of a pharmaceutically acceptable prodrug of acompound of Formula I to treat or prevent any of the above-identifieddisorders is provided. In one embodiment, use of a compositioncomprising a pharmaceutically acceptable prodrug of a compound ofFormula I to treat or prevent any of the above-identified disorders isprovided. In one embodiment, use of a pharmaceutically acceptableprodrug of a compound of Formula I in the preparation of a medicamentfor the treatment or prevention of any of the above-identified disordersis provided.

In one aspect, a compound of Formula I, or a pharmaceutically acceptablesalt or solvate thereof, or a composition comprising such a compound orpharmaceutically acceptable salt or solvate thereof, may be used incombination with another agent for the treatment of a disease or thetreatment of a symptom associated with a disease. In one embodiment, acompound of Formula I, or a pharmaceutically acceptable salt thereof, ora composition comprising such a compound or pharmaceutically acceptablesalt thereof, may be used in combination with another agent for thetreatment of a disease or the treatment of a symptom associated with adisease. In some embodiments of the use in combination with one or moreagents for the treatment of Alzheimer's disease, the one or more otheragents is selected from the group consisting of a cholinesteraseinhibitor, an NMDA receptor antagonist, an antioxidant, anantidepressant, an anxiolytic, an antipsychotic, an anti-Aβ peptidevaccine, an anti-Aβ peptide antibody, a retinoid X receptor activator, agamma secretase inhibitor, another BACE1 inhibitor, inhibitors ofβ-amyloid aggregation, inhibitors of tau aggregation, and tau kinaseinhibitors.

In one embodiment, a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, or a composition comprising such acompound or pharmaceutically acceptable salt or solvate thereof; in someembodiments a compound of Formula I, or a pharmaceutically acceptablesalt thereof, or a composition comprising such a compound orpharmaceutically acceptable salt thereof; may be used in combinationwith one or more agents for the treatment of Alzheimer's disease,wherein the one or more agents is selected from the group consisting ofdonepezil, galantamine, revastigmine, tactrine, memantine, vitamin E,citalopram, fluoxetine, paroseine, setraline, trazodone, nortriptyline,lorazepam, oxazepam, temazepam, aripiprazole, clozapine, haloperidol,olanzapine, quetiapine, risperidone, ziprasidone, bexarotene,bapineuzumab, solanezumab, clioquinol, resveratrol, methylene blue, IVimmunoglobulin, docosahexanenoic acid, latrepirdine, and davunetide.

Exemplary compounds as described herein, e.g. compounds of Formula I,are provided in Examples 1-14 below, including testing of their in vitroand/or in vivo biological activities and pharmaceutical properties (e.g.Example A, B and C).

Compound Forms and Derivatives

In one aspect, various forms or derivatives of compounds as describedherein are provided. In on example, a compound of Formula I may exist ina number of different forms or derivatives, for example, tautomers,isomers, racemic mixtures, prodrugs, active metabolites,pharmaceutically acceptable salts, pharmaceutically acceptable solvates,isotopically enhanced forms, conjugates, and other solid forms thereof,including different crystal forms, polymorphs or amorphous solids.

A compound as described herein, e.g. a compound of Formula I, can existin particular geometric, conformational or stereoisomeric forms. Thecompound of Formula I includes all such isomeric forms, including cis-and trans-isomers, atropisomers, (−)- and (+)-enantiomers,diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof,and other mixtures thereof, such as enantiomerically ordiastereomerically enriched mixtures. Such regioisomers andstereoisomers may be isolated in enriched form by standard separationmethods known to those skilled in the art. Additional asymmetric carbonatoms can be present in a substituent such as an alkyl group. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Compounds may also include regions that are sterically constrained suchthat atropisomers may be isolated by standard separation methods knownto those skilled in the art. Likewise, all tautomeric forms and mixturesof tautomers are included.

Optically active (R)- and (S)-isomers and d and l isomers can beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. Resolution of the racemates can beaccomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent; chromatography,using, for example a chiral HPLC column; or derivatizing the racemicmixture with a resolving reagent to generate diastereomers, separatingthe diastereomers via chromatography, and removing the resolving agentto generate the original compound in enantiomerically enriched form. Anyof the above procedures can be repeated to increase the enantiomericpurity of a compound. If, for instance, a particular enantiomer of acompound as described herein is desired, it can be prepared byasymmetric synthesis, or by derivatization with a chiral auxiliary,where the resulting diastereomeric mixture is separated and theauxiliary group cleaved to provide the desired enantiomers.Alternatively, where the molecule contains a basic functional group,such as an amino group, or an acidic functional group, such as acarboxyl group, diastereomeric salts can be formed with an appropriateoptically active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means known in the art, and subsequent recovery of theenantiomers in enriched form. In addition, separation of enantiomers anddiastereomers is frequently accomplished using chromatography employingchiral, stationary phases, optionally in combination with chemicalderivatization (e.g., formation of carbamates from amines).

A compound as described herein, e.g. a compound of Formula I, can existin a prodrug form. A prodrug of a compound as described herein is apharmaceutically acceptable derivative of a compound of Formula I thatreadily undergoes chemical changes under physiological conditions toprovide the compound as described herein (e.g. a compound of Formula I).It is understood that such prodrugs are effectively equivalent to acompound of Formula I, i.e. when such a prodrug is administered into asubject, such administration effectively encompasses the use of acompound of Formula I. Non-limiting examples of a pharmaceuticallyacceptable derivative or prodrug include pharmaceutically acceptableesters, phosphate esters or sulfonate esters thereof as well as otherderivatives of a compound as described herein which, upon administrationto a recipient, is capable of providing, either directly or indirectly,a compound as described herein (e.g. a compound of Formula I).Particularly favored derivatives or prodrugs are those that increase thebioavailability of a compound as described herein when such compound isadministered to a mammal (e.g., by allowing an orally administeredcompound to be more readily absorbed into the blood stream) or whichenhance delivery of the parent compound to a biological compartment(e.g., the brain or lymphatic system) relative to the parent species.

Prodrugs include a variety of esters (e.g. carboxylic acid ester) orprotected amines (e.g. acylated amine groups). Ester groups that aresuitable as prodrug groups are generally known in the art and includebenzyloxy, di(C₁₋₆)alkylaminoethyloxy, acetoxymethyl, pivaloyloxymethyl,phthalidoyl, ethoxycarbonyloxyethyl, 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, and C₁₋₆ alkoxy esters, optionally substituted by N-morpholinoand amide-forming groups such as di(C₁₋₆)alkylamino. In one example,ester prodrug groups include C₁₋₆ alkoxy esters. Those skilled in theart will recognize various synthetic methodologies that may be employedto form a pharmaceutically acceptable prodrug of the compound of FormulaI (e.g., via esterification of a carboxylic acid or hydroxyl group,acylation of an amine group).

In one example, the prodrug is suitable for treatment/prevention ofthose diseases and conditions that require the drug molecule to crossthe blood brain barrier. In one example, the prodrug enters the brain,where it is converted into the active form of the drug molecule. Inanother example, a prodrug is used to enable an active drug molecule toreach the inside of the eye after topical application of the prodrug tothe eye. Additionally, prodrugs can be converted to a compound asdescribed herein (e.g. a compound of Formula I) by chemical orbiochemical methods in an ex vivo environment. For example, a prodrugcan be slowly converted to the compound of Formula I when placed in atransdermal patch reservoir with a suitable enzyme or chemical reagent.

A compound as described herein, e.g. a compound of Formula I, when usedin vivo may form an active metabolite. Thus, such metabolites areprovided as pharmacologically active compounds or compounds that furthermetabolize to pharmacologically active compounds that are derivatives ofcompounds as described herein resulting from metabolic processes in thebody of a subject. Such metabolites are readily identified by those ofskill in the art, and may further be prepared similarly to the methodsas described herein, such that a suitable metabolite can be prepared andisolated for pharmaceutical use.

A compound as described herein, e.g. a compound of Formula I, can existin a pharmaceutically acceptable salt form. A compound of Formula I maybe prepared with relatively nontoxic acids or bases, depending on theparticular substituents found on the compounds described herein. Suchsalts and their preparation for use as pharmaceuticals are readily knownto those of skill in the art. Such salts may provide improvedproperties, e.g. solubility or pharmacokinetic properties, such that thepharmacological activity of the compound of Formula I is enhanced uponadministration to a subject. It is understood that such salts areeffectively equivalent to a compound of Formula I, i.e. when such a saltis administered into a subject, such administration effectivelyencompasses the use of a compound of Formula I. When a compound asdescribed herein (e.g. a compound of Formula I) contains relativelyacidic functionalities (e.g., —COOH group), base addition salts can beobtained by contacting the compound (e.g., neutral form of suchcompound) with a sufficient amount of the desired base, either neat orin a suitable inert solvent. Examples of pharmaceutically acceptablebase addition salts include lithium, sodium, potassium, calcium,ammonium, organic amino (e.g. ethylenediamine, diethylamine, piperazine,ethanolamine, diethanolamine, triethanolamine, tromethamine, choline,meglumine, benzathine, 4-phenylcyclohexylamine), zinc, magnesium andaluminum salts and the like. When a compound as described herein (e.g. acompound of Formula I) contains relatively basic functionalities (e.g.,amines), acid addition salts can be obtained, e.g., by contacting thecompound (e.g., neutral form of such compound) with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts includethose derived from inorganic acids like hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, monohydrogencarbonic, phosphoric,diphosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, thiocyanic, hydriodic and the like, as well as thesalts derived from relatively nontoxic organic acids like formic,acetic, alginic, propionic, isobutyric, ascorbic, aspartic, gentisic,galactaric, D-glucoheptanoic, D-gluconic, D-glucoronic, D-galactunoric,malic, maleic, malonic, benzoic, succinic, suberic, fumaric, glutaric,2-oxoglutaric, adipic, capric, caproic, caprylic, dodecylsulfuric,lactic, lactobionic, mandelic, naphthylene-1,5-disulfonic,naphthalene-2-sulfonic, 1-hydroxy-2-napthoic, orotic, oxalic, phthalic,pyroglutamic, glycerophosphoric, hippuric, benzenesulfonic,p-toluenesulfonic, camphorsulfonic, camphoric, cinnamic, citric,tartaric, methanesulfonic, nicotinic, ethanesulfonic,ethane-1,2-disulfonic, 2-hydroxyethanesulfonic, salicylic, lauric,oleic, palmitic, pamoic, sebacic, undecylenic, stearic and the like.Also included are salts of amino acids such as glutamate, lysinate,arginate and the like (see, for example, Berge et al., Journal ofPharmaceutical Science 1977, 66:1-19). Certain specific compounds asdescribed herein (e.g. a compound of Formula I) contain both basic andacidic functionalities that allow the compounds to be converted intoeither base or acid addition salts.

The neutral forms of the compounds can be regenerated, for example, bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound candiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound as described herein.

When a substituent includes a negatively charged oxygen atom “O” in“−COO⁻”, then the formula is meant to optionally include a proton or anorganic or inorganic cationic counterion. In one example, the resultingsalt form of the compound is pharmaceutically acceptable. Further, whena compound of Formula I includes an acidic group, such as a carboxylicacid group, e.g., written as the substituent “—COOH”, “—CO₂H” or“—C(O)₂H”, then the formula is meant to optionally include thecorresponding “de-protonated” form of that acidic group, e.g., “−COO⁻”,“—CO₂ ⁻” or “—C(O)₂”, respectively.

A compound as described herein, e.g. a compound of Formula I, can existin unsolvated forms as well as solvated forms, including hydrated forms.Such solvates may provide improved properties, e.g. solubility orpharmacokinetic properties, such that the pharmacological activity ofthe compound of Formula I is enhanced upon administration to a subject.It is understood that such solvated forms are effectively equivalent toa compound of Formula I, i.e. when such a solvate is administered into asubject, such administration effectively encompasses the use of acompound of Formula I.

A compound as described herein, e.g. a compound of Formula I, can existin multiple crystalline forms, i.e. polymorphs, or in an amorphous form,and a compound of Formula I encompasses all such forms of the compound.In general, all physical forms are of use in the methods contemplatedherein. Such physical forms may provide improved properties, e.g.solubility or pharmacokinetic properties, such that the pharmacologicalactivity of the compound of Formula I is enhanced upon administration ofthe particular form to a subject.

A compound as described herein, e.g. a compound of Formula I, cancontain natural or unnatural proportions of atomic isotopes at one ormore of the atoms that constitute such compounds. For example, thecompounds can be radiolabeled with radioactive isotopes, such as forexample tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopicvariations of a compound as described herein, whether radioactive ornot, are effectively encompassed by a compound as described herein,e.g., a compound in which one or more of the hydrogen atoms are replacedwith another stable isotope of hydrogen (i.e., deuterium) or aradioactive isotope (i.e., tritium), is expected to have similaractivity as it relates to BACE inhibition, and is effectively equivalentto a compound of Formula I. Such an isotopically enhanced compound maybe useful, for example, in detection of the compound in vivo or inbiological tissue, such as a radiolabelled compound containing ³H or ¹⁴Cto assess tissue distribution, or a positron emitting compoundcontaining ¹¹C, ¹⁵O, ¹³N, ¹⁸F or the like useful in positron emissiontomography for in vivo imaging. Similarly, a deuterated compound mayprovide the compound with greater metabolic stability relative to thenon-deuterated compound to provide improved pharmacokinetic properties.Such a compound is readily prepared by the methods as described herein,where suitable isotopically enhanced reagents may be used in place ofnon enhanced reagents. For example, alkyl groups may include isotopicvariants of hydrogen and carbon, such that methyl, for example, includes—CH₃, or may include the analogous structure in which any atoms caninclude any isotopes thereof, for example —CD₃, —¹⁴CH₃, and the like.

Pharmaceutical Compositions:

Pharmaceutical compositions are provided, including a compound asdescribed herein, e.g. a compound of Formula I, including any formsthereof, such as any isomers, polymorphs, pharmaceutically acceptablesalts or solvates thereof, and at least one pharmaceutically acceptablecarrier. A pharmaceutically acceptable carrier includes solvents, solidor liquid diluents, vehicles, adjuvants, excipients, glidants, binders,granulating agents, dispersing agents, suspending agents, wettingagents, lubricating agents, disintegrants, solubilizers, stabilizers,emulsifiers, fillers, preservatives (e.g., anti-oxidants), flavoringagents, sweetening agents, thickening agents, buffering agents, coloringagents and the like, as well as any mixtures thereof. Exemplary carriers(i.e., excipients) are described in, e.g., Handbook of PharmaceuticalManufacturing Formulations, Volumes 1-6, Niazi, Sarfaraz K., Taylor &Francis Group 2005, which is incorporated herein by reference in itsentirety. A pharmaceutical composition may include one or more compoundsof Formula I, including any forms thereof, such as any isomers,polymorphs, pharmaceutically acceptable salts or solvates thereof, inassociation with one or more pharmaceutically acceptable carrier andoptionally other active ingredients.

The compounds of Formula I may be administered orally, topically,parenterally, by inhalation or spray or rectally in dosage unitformulations containing at least one pharmaceutically acceptablecarrier. Parenteral administration includes percutaneous, subcutaneous,intravascular (e.g., intravenous), intramuscular, or intrathecalinjection or infusion techniques and the like. The pharmaceuticalcompositions containing a compound of Formula I may be in a formsuitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil. Formulations for oral use may also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of a compound of Formula I, or any salts orsolvates thereof, may also be in the form of oil-in-water emulsions. Theoily phase may be a vegetable oil or a mineral oil or mixtures of these.Suitable emulsifying agents may be naturally-occurring gums, for examplegum acacia or gum tragacanth, naturally-occurring phosphatides, forexample soy bean, lecithin, and esters or partial esters derived fromfatty acids and hexitol, anhydrides, for example sorbitan monooleate,and condensation products of the said partial esters with ethyleneoxide, for example polyoxyethylene sorbitan monooleate. The emulsionsmay also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative, a flavoringagent or a coloring agent. The pharmaceutical compositions may be in theform of a sterile, injectable, aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono-or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

A compound of Formula I may also be administered in the form ofsuppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

A compound of Formula I may be administered parenterally in a sterilemedium. The compound, depending on the vehicle and concentration used,can either be suspended or dissolved in the vehicle. Advantageously,adjuvants such as local anesthetics, preservatives and buffering agentscan be dissolved in the vehicle.

For disorders of the eye or other external tissues, e.g., mouth andskin, the formulations may be applied as a topical gel, spray, ointmentor cream, or as a scleral suppository, containing the active ingredientsin a total amount of, for example, 0.075 to 30% w/w, also 0.2 to 20% w/wand also 0.4 to 15% w/w. When formulated in an ointment, the activeingredients may be employed with either paraffinic or a water-miscibleointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound, which enhances absorption or penetrationof the active ingredient through the skin or other affected areas.Examples of such dermal penetration enhancers include dimethylsulfoxideand related analogs. The compound of Formula I can also be administeredby a transdermal device. In one example, topical administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane. The transdermal patch may include the compound in a suitablesolvent system with an adhesive system, such as an acrylic emulsion, anda polyester patch. The oily phase of the emulsions may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or oil or with both a fat and an oil. In oneexample, a hydrophilic emulsifier is included together with a lipophilicemulsifier, which acts as a stabilizer. In one example, both an oil anda fat are included. Together, the emulsifier(s) with or withoutstabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily, dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof compounds as described herein include Tween 60, Span 80, cetostearylalcohol, myristyl alcohol, glyceryl monostearate, and sodium laurylsulfate, among others. The choice of suitable oils or fats for theformulation is based on achieving the desired cosmetic properties, sincethe solubility of the active compound in most oils likely to be used inpharmaceutical emulsion formulations is very low. In one example, thecream is a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. In one example, the anti-inflammatory active ingredientsare present in such formulations in a concentration of 0.5 to 20%, alsoabout 0.5 to 10% and also about 1.5% w/w. For therapeutic purposes, theactive compounds, i.e. a compound of Formula I, are ordinarily combinedwith one or more adjuvants appropriate to the indicated route ofadministration. The compound may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets may contain a controlled-release formulation as maybe provided in a dispersion of active compound in hydroxypropylmethylcellulose. Formulations for parenteral administration may be in the formof aqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules having one or more of the carriers ordiluents mentioned for use in the formulations for oral administration.The compound may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

Formulations suitable for inhalation or insufflation include solutionsand suspensions in pharmaceutically acceptable aqueous or organicsolvents, or mixtures thereof, and powders. The liquid or solidcompositions may contain suitable pharmaceutically acceptable excipientsas describe above. The compositions may be administered by oral or nasalrespiratory route for local or systemic effect. Compositions may benebulized by use of inert gases or vaporized, and breathed directly fromthe nebulizing/vaporizing device or the nebulizing device may beattached to a facemask tent or intermittent positive pressure-breathingmachine.

Dosage levels of the order of from about 0.005 mg to about 100 mg perkilogram of body weight per day are useful in the treatment of thediseases and conditions described herein (e.g., about 0.35 mg to about 7g per human patient per day, based on an average adult person weight of70 kg). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient. The daily dose can be administered in one tofour doses per day. In one example, in the case of skin conditions, atopical preparation of a compound of Formula I may be applied to theaffected area one to four times a day.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It may be convenient toformulate the animal feed and drinking water compositions so that theanimal takes in a therapeutically appropriate quantity of thecomposition along with its diet. It may also be convenient to presentthe composition as a premix for addition to the feed or drinking water.

A compound as described herein, e.g. a compound of Formula I, can beformulated as described herein in combination with one or more otheragents, for example one or more other agents for the treatment ofAlzheimer's disease. For example, formulations may include a compound ofFormula I and one or more other agents selected from the groupconsisting of a cholinesterase inhibitor, an NMDA receptor antagonist,an antioxidant, an antidepressant, an anxiolytic, an antipsychotic, ananti-Aβ peptide vaccine, an anti-Aβ peptide antibody, a retinoid Xreceptor activator, a gamma secretase inhibitor, another BACE1inhibitor, inhibitors of β-amyloid aggregation, inhibitors of tauaggregation, and tau kinase inhibitors. In one example, a formulationincludes a compound of Formula I and one or more agents selected fromthe group consisting of donepezil, galantamine, revastigmine, tactrine,memantine, vitamin E, citalopram, fluoxetine, paroseine, setraline,trazodone, nortriptyline, lorazepam, oxazepam, temazepam, aripiprazole,clozapine, haloperidol, olanzapine, quetiapine, risperidone,ziprasidone, bexarotene, bapineuzumab, solanezumab, clioquinol,resveratrol, methylene blue, IV immunoglobulin, docosahexanenoic acid,latrepirdine, and davunetide.

Methods of Use:

BACE1 involvement in the processing of APP provides a suitable drugtarget for the treatment of diseases associated with Aβ peptidetoxicity. A BACE1 inhibitor can be used to reduce the amount of variousproducts of the processing of amyloid precursor protein in vivo,including the reduction of sAPPβ, CTFβ, Aβ-40 and Aβ-42, as well asreduction in or prevention of Aβ peptide aggregation, oligomerization,fibrillization or plaque formation. Reduction of levels of Aβ peptideincludes reduction in levels of soluble Aβ peptide and/or reduction inlevels of insoluble Aβ peptide aggregates (Aβ plaques). In one example,compounds as described herein are useful in the reduction of sAPPβ,CTFβ, Aβ-40 and Aβ-42 in a mammalian subject, including in the brain ofa mammalian subject. In one example, compounds as described herein areuseful in the prevention of Aβ peptide aggregation, oligomerization,fibrillization or plaque formation in a mammalian subject including inthe brain of a mammalian subject. In one example, the resultingreduction of Aβ-42 in particular is desirable to treat a variety ofdesease where high levels of Aβ-42 are detrimental. In one example,compounds as described herein are useful in the reduction in the levelsof Aβ plaques in the brain. In one example, compounds as describedherein are useful in the reduction in or prevention of Aβ peptideaggregation, oligomerization, fibrillization or plaque formation in thebrain. BACE2 is involvement in the processing of pancreatic β-cellsprovides a suitable drug target, for example, in the treatment of type 2diabetes.

The variety of diseases associated with Aβ peptide toxicity, or diseasesamenable to treatment with a BACE1 and/or BACE2 inhbitor includes, forexample, neurological diseases, such as Alzheimer's disease (includingany disorders associated with Alzheimer's disease, such as dementia,attention deficit, depression, agitation, mild cognitive impairment,cognitive decline, memory loss, senility, neurodegeneration, olfactoryimpairment), diffuse Lewy body type Alzheimer's disease, Parkinson'sdisease (including dementia associated with Parkinson's disease),frontotemporal dementias with parkinsonism, progressive supranuclearpalsy (including dementia associated with supranuclear palsy), corticalbasal degeneration (including dementia associated with cortical basaldegeneration), dementia with Lewy bodies, presenile dementia, seniledementia, multi-infarct dementia, dementia of mixed vascular anddegenerative origin, mild cognitive impairment, Down syndrome (includingdementia and cognitive impairment associated with Down syndrome),hereditary cerebral hemorrhage with amyloidosis of the Dutch-Type,cerebral amyloid angiopathy, amyotrophic lateral sclerosis, Huntington'sdisease, and demyelinating diseases (including multiple sclerosis,idiopathic inflammatory demyelinating disease, chronic inflammatorydemyelinating polyneuropathy, Guillain-Barre syndrome, progressivemultifocal leukoencephalopathy, and Charcot-Marie-Tooth Disease); otherCNS disorders, such as traumatic brain injury, brain inflammation,spinal cord injury, and nerve injury; anxiety disorders (includingobsessive-compulsive disorder, general anxiety disorder andpost-traumatic disorder); ocular diseases including glaucoma andage-related macular degeneration; cardiovascular diseases such asmyocardial infarction, arterial thrombosis, transient ischemic attack,and stroke (including dementia associated with stroke andneurodegeneration associated with stroke); other amyloidoses, such asfamilial amyloidotic polyneuropathy, hemodialysis associated amyloidosis(accumulation of β2-microglobulin and complications arising therefrom);prion diseases such as Creutzfeldt-Jakob disease,Gerstmann-Stráussler-Scheinker syndrome, scrapie (including Kuru scrapieand animal scrapie), and bovine spongiform encephalitis; cancers, suchas glioblastoma multiforme, multiple myeloma, malignant melanoma, Kaposisarcoma, and breast cancer; autoimmune diseases such as rheumatoidarthritis, Sjogren syndrome, lupus erythematosus, and Graves disease;inflammatory diseases such as inclusion body myositis, dermatomyositis,macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatousarthritis, and inflammatory reactions; and other diseases, includingnarcolepsy, type 2 diabetes, hypertension, Wilson's disease, Whipple'sdisease, spinocerebellar ataxia 1, spinocerebellar ataxia 7, andKostmann disease.

In one example, compounds of Formula I can be used to reduce in vivolevels of any one or more of sAPPβ, CTFβ, Aβ-40 and Aβ-42. In oneexample, compounds of Formula I can be used to reduce levels of any oneor more of sAPPβ, CTFβ, Aβ-40 and Aβ-42 in the brain. In one example,compounds of Formula I can be used to reduce the levels of of Aβ plaquesin the brain.

A compound as described herein is useful in the treatment and/orprevention of a disease selected from the group consisting ofneurological diseases, such as Alzheimer's disease (including anydisorders associated with Alzheimer's disease, such as dementia,attention deficit, depression, agitation, mild cognitive impairment,cognitive decline, memory loss, senility, neurodegeneration, olfactoryimpairment), diffuse Lewy body type Alzheimer's disease, Parkinson'sdisease (including dementia associated with Parkinson's disease),frontotemporal dementias with parkinsonism, progressive supranuclearpalsy (including dementia associated with supranuclear palsy), corticalbasal degeneration (including dementia associated with cortical basaldegeneration), dementia with Lewy bodies, presenile dementia, seniledementia, multi-infarct dementia, dementia of mixed vascular anddegenerative origin, mild cognitive impairment, Down syndrome (includingdementia and cognitive impairment associated with Down syndrome),hereditary cerebral hemorrhage with amyloidosis of the Dutch-Type,cerebral amyloid angiopathy, amyotrophic lateral sclerosis, Huntington'sdisease, and demyelinating diseases (including multiple sclerosis,idiopathic inflammatory demyelinating disease, chronic inflammatorydemyelinating polyneuropathy, Guillain-Barre syndrome, progressivemultifocal leukoencephalopathy, and Charcot-Marie-Tooth Disease); otherCNS disorders, such as traumatic brain injury, brain inflammation,spinal cord injury, and nerve injury; anxiety disorders (includingobsessive-compulsive disorder, general anxiety disorder andpost-traumatic disorder); ocular diseases including glaucoma andage-related macular degeneration; cardiovascular diseases such asmyocardial infarction, arterial thrombosis, transient ischemic attack,and stroke (including dementia associated with stroke andneurodegeneration associated with stroke); other amyloidoses, such asfamilial amyloidotic polyneuropathy, hemodialysis associated amyloidosis(accumulation of β2-microglobulin and complications arising therefrom);prion diseases such as Creutzfeldt-Jakob disease,Gerstmann-Stráussler-Scheinker syndrome, scrapie (including Kuru scrapieand animal scrapie), and bovine spongiform encephalitis; cancers, suchas glioblastoma multiforme, multiple myeloma, malignant melanoma, Kaposisarcoma, and breast cancer; autoimmune diseases such as rheumatoidarthritis, Sjogren syndrome, lupus erythematosus, and Graves disease;inflammatory diseases such as inclusion body myositis, dermatomyositis,macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatousarthritis, and inflammatory reactions; and other diseases, includingnarcolepsy, type 2 diabetes, hypertension, Wilson's disease, Whipple'sdisease, spinocerebellar ataxia 1, spinocerebellar ataxia 7, andKostmann disease.

The methods of use of a compound or composition thereof as describedherein in treatment of various diseases includes administering to amammalian subject (e.g., human) in need thereof a therapeuticallyeffective amount of a compound of Formula I, or pharmaceuticallyacceptable salt or solvate thereof, including any form thereof, or acomposition comprising such a compound, pharmaceutically acceptable saltor solvate thereof, including any form thereof.

Activity of Compounds:

Compounds as described herein, e.g., a compound of Formula I, are testedfor their activity in vitro to inhibit cleavage of APP between Met595and Asp596 numbered for the APP695 isoform, or a mutant thereof, or at acorresponding site of a different isoform, such as APP751 or APP770, ora mutant thereof. Inhibitory activity is demonstrated in one of avariety of inhibition assays, for example whereby cleavage of an APPsubstrate in the presence of BACE1 enzyme is analyzed in the presence ofthe inhibitory compound, under conditions normally sufficient to resultin cleavage at the BACE1 cleavage site. Reduction of APP cleavage at theBACE1 cleavage site compared with an untreated or inactive control iscorrelated with inhibitory activity. Assay systems that can be used todemonstrate efficacy of the compounds as described herein are known.Similar assays can be used to assess activity of BACE2 and otherproteases for comparison, such as Cathepsin D. Representative assaysystems are described, for example, in U.S. Pat. Nos. 5,942,400 and5,744,346, PCT publication number WO 2011/069934, PCT publication numberWO 2011/029803, and PCT Publication Number WO 2007047306, thedisclosures of which are hereby incorporated by reference with respectto such assays.

The enzymatic activity of BACE1 and the production of Aβ can be analyzedusing natural, mutated, and/or synthetic APP substrates, natural,mutated, and/or synthetic enzyme, and a compound as described herein.The analysis can involve a biochemical assay, or a cellular assayinvolving primary or secondary cells expressing native, mutant, and/orsynthetic APP and enzyme. Detection of enzymatic activity can be byanalysis of at least one of the cleavage products, for example, byimmunoassay, fluorometric or chromogenic assay, HPLC, or other means ofdetection. Inhibitory compounds are determined as those able to decreasethe amount of BACE1 cleavage product produced in comparison to acontrol, where BACE1 mediated cleavage in the reaction system isobserved and measured in the absence of inhibitory compounds. Theefficacy of the compounds as described herein is determined as apercentage inhibition at a particular concentration, or the percentageinhibition as a function of compound concentration can be used tocalculate an IC₅₀ for the compound in a particular assay.

A compound as described herein is useful in inhibiting the proteaseactivity of BACE, including BACE1 and/or BACE2. Protease activity can bedetermined using any suitable assay, as are known in the art ordescribed herein, where such assays typically employ a suitable proteasesubstrate as known in the art or as described herein. In one example, amethod (e.g., an in vitro assay) is provided that includes: (i)contacting a compound of Formula I with a BACE kinase, thereby forming amixture. The method may further include (ii) contacting the mixture witha protease substrate (e.g., peptide substrate) thereby forming an amountof protease cleavage product. The method can further include (iii)measuring the amount of protease cleavage product. The amount ofprotease cleavage product may be measured using a detection reagent.Suitable detection reagents can include a metal reagent, such as alanthanoid (e.g., Eu-63), a radioactive probe, a labeled (e.g.,fluorescently labelled) antibody and combinations thereof. Exemplaryassays include a fluorescence resonance energy transfer (FRET) assay(e.g., TR-FRET), an AlphaScreen® assay, or the like. Examples of suchassays are described in Example A. In one example, a compound of FormulaI is used as a reference standard to determine the in vitro activity ofother compounds in a protease assay as described above. Thus, in anotherexample, the compound of Formula I is used in an in vitro assay foridentifying candidate compounds that are capable of inhibiting BACEprotease activity, including BACE1 and/or BACE2 activity.

The activity of a compound as described herein can also be assessed inother proteases, including cathepsin D, cathepsin E, renin and pepsin.In vitro assays for the determination of such other protease activitiesare known in the art and exemplary assay formats are described herein(see e.g., Example A). Assays for BACE1 and other protease activitiesare also described, for example, in PCT publication number WO2011/069934, PCT publication number WO 2011/029803, PCT publicationnumber WO 2007/047306, the disclosures of which are hereby incorporatedby reference with respect to such assays.

Certain compounds as described herein, e.g. compounds of Formula I,exhibit various in vitro cellular activities, such as the inhibition ofBACE1 activity in a suitable cellular system, or cellular systems toassess other proteases, including BACE2 and cathepsin D. For example,numerous cell-based assays can be used to analyze BACE1 activity and/orprocessing of APP to release Aβ. Contact of an APP substrate with aBACE1 enzyme within the cell and in the presence or absence of acompound as described herein can be used to demonstrate BACE1 inhibitoryactivity of the compound. In one example, the assay in the presence of auseful inhibitory compound provides at least about 10% inhibition of theenzymatic activity, as compared with a non-inhibited control. In oneexample, cells that naturally express BACE1 are used. Alternatively,cells are modified to express a recombinant BACE1 or synthetic variantenzyme. The APP substrate can be added to the culture medium or isexpressed in the cells. Cells that naturally express APP, variant ormutant forms of APP, or cells transformed to express an isoform of APP,mutant or variant APP, recombinant or synthetic APP, APP fragment, orsynthetic APP peptide or fusion protein containing the BACE1 APPcleavage site can be used, provided that the expressed APP is permittedto contact the enzyme and enzymatic cleavage activity can be analyzed.Human cell lines that normally process Aβ from APP provide useful meansto assay inhibitory activities of the compounds employed in the methodsof treatment as described herein. Production and release of Aβ and/orother cleavage products into the culture medium can be measured, forexample by immunoassay, such as Western blot or enzyme-linkedimmunoassay (EIA) such as by ELISA. For example, the inhibition of BACE1activity can be assessed in human embryonic kidney cell line HEKp293(ATCC Accession No. CRL-1573) transfected with APP751 containing thenaturally occurring double mutation Lys651Met652 to Asn651Leu652,commonly called the Swedish mutation shown to overproduce Aβ (Citron etal., Nature 1992, 360:672-674). Aβ levels in treated or untreated cellsare measured by immunoassay with Aβ specific antibodies, which can beassessed for the compounds as described herein (see e.g., Example A).Similarly, inhibition of BACE2 can be assessed by monitoring thecleavage of TMEM27, for example in an INS1E rat cell line. Assays arealso described, for example, in PCT publication number WO 2011/069934,PCT publication number WO 2011/029803, PCT publication number WO2007/047306, the disclosures of which are hereby incorporated byreference with respect to such assays.

Although both neural and non-neural cells process and release Aβ, levelsof endogenous BACE1 activity are low and often difficult to detect byEIA. The use of cell types known to have enhanced BACE1 activity,enhanced processing of APP to Aβ, and/or enhanced production of Aβ aresuited to use in cellular assays. For example, transfection of cellswith the Swedish Mutant form of APP (APP-SW), with APP-KK, or withAPP-SW-KK provides cells having enhanced BACE1 activity and producingamounts of AP that can be readily measured. In such assays, for example,the cells expressing APP and BACE1 are incubated in a culture mediumunder conditions suitable for BACE1 enzymatic activity at its cleavagesite on the APP substrate. On exposure of the cells to the compoundinhibitor employed in the methods of treatment, the amount of Aβreleased into the medium and/or the amount of CTFβ fragments of APP inthe cell lysates is reduced as compared with the control. The cleavageproducts of APP can be analyzed, for example, by immune reactions withspecific antibodies, as discussed above. In one example, cells foranalysis of BACE1 activity include primary human neuronal cells, primarytransgenic animal neuronal cells where the transgene is APP, and othercells such as those of a stable human embryonic kidney cell line HEKp293(ATCC Accession No. CRL-1573) expressing APP, for example, APP-SW. Inone example, the the level of Aβ in HEKp293 cells transfected withAPP751 treated with a compound of Formula I will be less than 90%, lessthan 80%, less than 70%, less than 60%, less than 50%, less than 40%,less than 30%, less than 20%, less than 10%, less than 5%, or less than1% of the level in control cells that are not treated with compound.

A compound as described herein can exhibit in vivo biological activity,such as reduction in the levels of Aβ peptide in a mouse model. Variousanimal models can be used to analyze BACE1 activity and/or processing ofAPP to release Aβ, as described above. For example, transgenic animalsexpressing APP substrate and BACE1 enzyme can be used to demonstrateinhibitory activity of the compounds as described herein. Certaintransgenic animal models have been described, for example, in U.S. Pat.Nos. 5,877,399, 5,612,486, 5,387,742, 5,720,936, 5,850,003, 5,877,015,and 5,811,633, and in Games et al., Nature 1995, 373:523. Animals thatexhibit characteristics associated with the pathophysiology ofAlzheimer's disease are suitable for use in assessing in vivo biologicalactivity. Administration of the compounds as described herein to thetransgenic mice described herein provides an alternative method fordemonstrating the inhibitory activity of the compounds. In one example,administration of the compounds as described herein in apharmaceutically effective carrier and via an administrative route thatreaches the target tissue in an appropriate therapeutic amount issuitable. For example, following peritoneal injection of a compound ofFormula I (e.g., at a dose of about 50 mg, about 100 mg, about 200 mg orabout 300 mg/kg), or a vehicle control, plasma and brain tissue can beharvested and assessed for the level of Aβ peptide (Aβ-40 and/or Aβ-42)by immunoassay detection. Assays are described, for example, in PCTpublication number WO 2011/115938 and PCT publication number WO2007/047306, the disclosures of which are hereby incorporated byreference with respect to such assays. In one example, the level of Aβpeptide in the brain or plasma of mice treated with a compound ofFormula I will be less than 90%, less than 80%, less than 70%, less than60%, less than 50%, less than 40%, less than 30%, less than 20%, lessthan 10%, less than 5%, or less than 1% of the Aβ peptide levels fromthe brain or plasma of control mice that are not treated with compound.

Synthesis of the Compounds:

The compounds as described herein, e.g. compounds of Formula I, can beprepared using methods known in the art of organic synthesis and thosedescribed herein in the Examples. The starting materials and variousintermediates may be obtained from commercial sources, prepared fromcommercially available compounds, and/or prepared using known syntheticmethods. For example, the compounds as described herein, as well as allintermediates, can be synthesized by processes using either solution orsolid phase techniques. Exemplary procedures for preparing compounds asdescribed herein are outlined in the following schemes. It is understoodthat for the exemplary procedures, variations and modifications arereadily available, for example, any of solvents, reaction times,reagents, temperatures, work up conditions, or other reaction parametersmay be varied employing alternate solvents, reagents, reaction times,temperatures, work up conditions, and the like, as are readily availableto one skilled in the art.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and P. G. M. Wuts, Protecting Groups inOrganic Synthesis, Third Edition, Wiley, New York, 1999, and referencescited therein.

The sulfinamide compound C, which can be used in the synthesis of acompound of Formula I, is prepared from compound A, a suitable acetyl,bromo substituted ring A₂, and 2-methylpropane-2-sulfinamide compound B,in one step according to Scheme 1.

Compound A (A₂, R⁵ and n are as described for compounds of Formula I) isreacted with 2-methylpropane-2-sulfinamide B (wherein the wavy line bondto the sulfur indicates this compound can be a racemic mixture, or thespecific R or S isomer) and tetraethoxytitanium in a suitable solvent,such as THF, with heating (e.g. 75° C.) to provide compound C.Alternatively, compound A can be replaced with a compound alreadycontaining ring A₃ (as described for compounds of Formula I), either asa compound readily available, or by reacting compound A to replace thebromine with ring A₃ via a Suzuki reaction with a suitable boronic acid(as described in Scheme 8).

The compound J, which can be used in the synthesis of a compound ofFormula I wherein A₁ is carbocyclic or heterocyclic, Y is O, R² and R³are H, and R¹ is methyl, is prepared from compound A, a suitable acetyl,bromo substituted ring A₂, and a cyclic ketone compound D, in six stepsaccording to Scheme 2.

Compound A (A₂, R⁵ and n are as described for compounds of Formula I)can be treated with base (e.g. LiHMDS) in a suitable solvent, such asTHF, at low temperature (e.g. −78° C.) and reacted with Compound D (A₁,R⁴ and m are as described for compounds of Formula I) to providecompound E upon warming to room temperature. The OH of compound E isprotected with a suitable protecting group, for example with TBDMSgroup, by reacting with tert-butyldimethylsilyl triflate in the presenceof 2,6-lutidine in CH₂Cl₂ at low temperature (e.g. 0° C.), then warmingto room temperature to provide compound F. Compound F is combined withtetraethoxytitanium and 2-methylpropane-2-sulfinamide B (wherein thewavy line bond to the sulfur indicates this compound can be a racemicmixture, or the specific R or S isomer) in, for example, dry THF andheated, e.g. to reflux, to provide compound G, which is then treatedwith a Grignard reagent, e.g. methyl magnesium bromide in, for example,THF and ether to provide compound H (when the S or R isomer of B is usedin Step 3, this reaction can be done under conditions to provide aspecific stereoisomer on the chiral carbon as indicated by the secondwavy line). The nitrogen of Compound H is deprotected, for examplestepwise with TBAF in THF at room temperature followed by HCl in dioxaneto provide compound 1, which is cyclized to form the dihydro-oxazine J,for example by heating in a sealed tube with cyanic bromide, e.g. at 65°C. for 18 hours.

The compound T, which can be used in the synthesis of a compound ofFormula I wherein A₁ is cyclobutane, cyclopentane or cyclohexane, Y isS, R² and R³ are H, and R¹ is methyl, is prepared from carboxylic acidcompound K, in nine steps according to Scheme 3.

C₄₋₆ Cycloalk-1-enecarboxylic acid K is reacted with a suitable reducingagent (e.g. lithium aluminum hydride) in ether or other suitablesolvent, heating to reflux under nitrogen. The resulting alcohol L isreacted with a suitable bromination reagent, such asdibromo(triphenyl)-phosphane, in CH₂Cl₂ or other suitable solvent toprovide the bromomethyl substituted cycloalkene M, which is furtherreacted with zinc, 1,2-dibromoethane and chloro(trimethyl)silane, forexample in dry THF, to provide the bromo zinc compound N. A suitablesulfinamide compound C (A₂, R⁵ and n are as described for compounds ofFormula I, prepared by the methods provided in Scheme 1) is reacted withcompound N, where the reaction is performed by dropwise addition of N toa solution of compound C with AlMe₃ in THF or other suitable solvent atlow temperature (e.g. −78° C.) to provide compound O. The compound C canbe either a racemic mixture, or can be the specific stereoisomer at theindicated wavy line bond to the sulfur, where under suitable conditionsthe stereoisomer may selectively provide a particular stereoisomer incompound O at the indicated wavy line bond to the stereocenter carbon.Note that, alternatively, compound C can be substituted with a suitablecompound already including ring A₃ in this reaction. Compound O isreacted with HCl in dioxane in a suitable solvent such as MeOH toprovide compound P, which is reacted with benzoyl isothiocyanate 44 indry THF or other suitable solvent to provide compound Q. Cyclization ofcompound Q to provide the substituted dihydro-thiazine R is performed atlow temperature (e.g. 0° C.), reacting with iodine in a suitable solventsuch as dry CH₂Cl₂. Compound R can be reacted with sodiumcyanoborohydride, for example in MeOH and HOAc, to provide compound S,which is then reacted with hydrazine in a suitable solvent, such asCH₂Cl₂, to remove the amine protecting group, providing compound T.

The compound Z, which can be used in the synthesis of a compound ofFormula I wherein A₁ is oxetane, Y is S, R² and R³ are H, and R¹ ismethyl, is prepared from 2-methylenepropane-1,3-diol 53 in nine stepsaccording to Scheme 4.

2-methylenepropane-1,3-diol 53 is converted in three steps to providebromo-[2-[[tert-butyl(diphenyl)silyl]oxymethyl]allyl]zinc 56 by themethods described in Example 4 below. A suitable sulfinamide compound C(A₂, R⁵ and n are as described for compounds of Formula I, prepared bythe methods provided in Scheme 1) is reacted withbromo-[2-[[tert-butyl(diphenyl)silyl]oxymethyl]allyl]zinc 56, where thereaction is performed by dropwise addition of 56 to a solution ofcompound C with AlMe₃ in THF or other suitable solvent at lowtemperature (e.g. −78° C.) to provide compound U. The compound C can beeither a racemic mixture, or can be a specific stereoisomer at theindicated wavy line bond to the sulfur, where under suitable conditionsthe stereoisomer may selectively provide a specific stereoisomer incompound U at the indicated wavy line bond to the chiral carbon. Notethat, alternatively, compound C can be substituted with a suitablecompound already including ring A₃ in this reaction. Compound U isreacted with HCl in dioxane in a suitable solvent such as MeOH toprovide compound V, which is reacted with O-(9H-fluoren-9-yl)methylcarbonisothiocyanatidate 59 in dry THF or other suitable solvent toprovide compound W, which is reacted with iodine in a suitable solventsuch as THF to provide compound X. Compound X can be reacted withpotassium carbonate in a suitable solvent, such as dioxane/water, toform the oxetane spirocycle, providing Compound Y, which is deprotectedby reaction with piperidine in a suitable solvent such as CH₂Cl₂, toprovide Compound Z.

The compound FF, which can be used in the synthesis of a compound ofFormula I wherein A₁ is carbocyclic or heterocyclic, Y is S, R² and R³are H, and R¹ is methyl, is prepared from (4-methoxyphenyl)methanethiol65 and Compound E (see Scheme 2) in six steps according to Scheme 5.

Compound E (prepared as described in Scheme 2; A₂, A₁, R⁴, R⁵, m and nare as described for compounds of Formula I) is reacted with(4-methoxyphenyl)methanethiol 65 and dibromocopper in CH₃NO₂, to provideCompound AA, which is then reacted with tetraethoxytitanium and2-methylpropane-2-sulfinamide B (wherein the wavy line bond to thesulfur indicates this compound can be a racemic mixture, or the specificR or S isomer) in a suitable solvent such as dry THF and heated, e.g. toreflux, to provide compound BB. Compound BB is treated with a Grignardreagent, e.g. methyl magnesium bromide in a suitable solvent such as THFand ether to provide compound CC (when the S or R isomer of B is used inStep 2, this reaction can be done under conditions to provide a specificstereoisomer on the chiral carbon as indicated by the second wavy line).The nitrogen is deprotected by reacting with HCl in dioxane in asuitable solvent, such as CH₂Cl₂, to provide Compound DD, which uponreacting with anisole in TFA results in Compound EE. Compound EE is thenreacted with cyanic bromide and DIEA in a suitable solvent such as EtOHfor provide the desired compound FF.

The compound PP, which can be used in the synthesis of a compound ofFormula I wherein A₁ is cyclopropane, Y is O, R² and R³ are H, and R¹ ismethyl, is prepared from ethane-1,2-diol 76 and Compound GG in ninesteps according to Scheme 6.

Compound GG (A₂, R⁵ and n are as described for compounds of Formula I)is reacted with ethane-1,2-diol 76 and p-toluenesulfonic acid in asuitable solvent, such as toluene to provide Compound HH. Compound HH iscombined with tetraisoproxytitanium in a suitable solvent such asTHF/Et₂O and reacted with EtMgBr to provide Compound II, which is thenreacted with HCl, for example in MeOH to provide Compound JJ. Theresulting OH group is protected by reacting, for example, withtert-butyldimethylsilyl triflate and 2,6-lutedine in a suitable solventsuch as CH₂Cl₂, to provide compound KK, which is then reacted withtetraethoxytitanium and 2-methylpropane-2-sulfinamide B (wherein thewavy line bond to the sulfur indicates this compound can be a racemicmixture, or the specific R or S isomer) in a suitable solvent such asdry THF and heated, e.g. to reflux, to provide Compound LL. Reaction ofCompound LL in a suitable solvent such as THF under nitrogen at lowtemperature (e.g. −20° C.) with dropwise addition of MeLi in etherresults in Compound MM, which is then reacted with tetrabutylammoniumfluoride in a suitable solvent such as THF to provide Compound NN. Thenitrogen is deprotected with HCl in dioxane in a suitable solvent suchas CH₂Cl₂ to provide Compound OO, which is reacted with cyanic bromidein a suitable solvent such as EtOH for provide the desired compound PP.

The compound XX, which can be used in the synthesis of a compound ofFormula I wherein A₁ is carbocyclic or heterocyclic, Y is O, R² and R³are F, and R¹ is methyl, is prepared from Compound QQ in seven stepsaccording to Scheme 7.

Magnesium and chloro(trimethyl)silane are combined in a suitable solventsuch as THF and reacted with dropwise addition of Compound QQ (A₂, R⁵and n are as described for compounds of Formula I) at low temperature(e.g. 0° C.) to provide Compound RR. Compound D (A₁, R⁴ and m are asdescribed for compounds of Formula I) is added to a solution oftetrachlorotitanium in a suitable solvent such as CH₂Cl₂ under nitrogenat e.g. −78° C., then reacted with dropwise addition of Compound RR toprovide Compound SS. Compound SS is dissolved in a suitable solvent suchas HOAc and MeOH, with addition of KBr, then1-chloropyrrolidine-2,5-dione, and reacted at elevated temperature (e.g.60° C.), resulting in Compound TT. Compound TT is then reacted withtetraethoxytitanium and 2-methylpropane-2-sulfinamide B (wherein thewavy line bond to the sulfur indicates this compound can be a racemicmixture, or the specific R or S isomer) in a suitable solvent such asdry THF and heated, e.g. to reflux, to provide Compound UU. Reaction ofCompound UU in THF under nitrogen at low temperature (e.g. 0° C.) withdropwise addition of CH₃MgBr in ether results in Compound VV. Thenitrogen is deprotected with HCl in dioxane in a suitable solvent suchas CH₂Cl₂ to provide Compound WW, which is reacted with cyanic bromidein a suitable solvent such as EtOH for provide the desired compound XX.

The Compound AB (e.g. Compounds J, T, Z, FF, PP or XX prepared asdescribed in Schemes 2-7) can be reacted with a suitable boronic acidCompound AC or Compound AD (Suzuki reaction) to provide Compound AE orCompound AF, e.g. a compound of Formula I wherein L is a direct bond or—CH═CH—, respectively, R¹ is methyl and R² and R³ are both hydrogen orboth F, in one step according to Scheme 8/8a.

The bromine on ring A₂ of Compound AB (e.g. Compounds J, T, Z, FF, PP orXX prepared as described in Schemes 2-7, R² and R³ are either both H orboth F, Y, A₁, A₂, R⁴, R⁵, m and n are as described for compounds ofFormula I) can be replaced in a Suzuki reaction with a suitable boronicacid AC or AD (A₃, R⁶ and p are as described for compounds of Formula I,B(OR)₂ is e.g. B(OH)₂ or a suitable ester thereof), reacting in asuitable solvent, such as DME/water, with a suitable base, such ascesium carbonate, and a suitable palladium catalyst, such as1,1′-bis(diphenylphosphino)ferrocine palladium (II) dichloride, withheating (e.g. 90° C.) under nitrogen, to provide the desired compound AEor AF.

The Compound AB (e.g. Compounds J, T, Z, FF, PP or XX prepared asdescribed in Schemes 2-7) can be reacted to convert the bromine to anamine, and subsequently modified to provide Compound AL, e.g. a compoundof Formula I wherein L is —NH—C(O)—, R¹ is methyl and R² and R³ are bothhydrogen or both F, in five steps according to Scheme 9.

The free amine of Compound AB (e.g. Compounds J, T, Z, FF, PP and XXprepared as described in Schemes 2-7, R² and R³ are either both H orboth F, Y, A₁, A₂, R⁴, R⁵, m and n are as described for compounds ofFormula I) is Boc protected by reacting with tert-butoxycarbonyltert-butyl carbonate and N-ethyl-N-isopropylpropan-2-amine in a suitablesolvent such as CH₂Cl₂. The resulting Compound AG is reacted with sodiumazide, sodium ascorbate, copper sulfate andN1,N2-dimethylcyclohexane-1,2-diamine in a suitable solvent such asEtOH/water to provide the azido Compound AH, which is converted to theamino Compound AI by hydrogenation, for example reacting with H₂ and 10%Pd/C catalyst in a suitable solvent such as EtOH. Reaction of CompoundAI with a suitable carboxylic acid Compound AJ (A₃, R⁶ and p are asdescribed for compounds of Formula I) in the presence of[benzotriazol-1-yloxy(dimethylamino)methylene]-dimethyl-ammoniumhexafluorophosphate and N-ethyl-N-isopropyl-propan-2-amine in a suitablesolvent such as DMF results in the amide linked Compound AK which issubsequently deprotected with TFA, for example in CH₂Cl₂, to provide thedesired Compound AL.

Alternatively, Compound AI as prepared by the methods of Scheme 9 can bereacted in two steps to provide Compound AO, e.g. a compound of FormulaI wherein L is —NH—CH₂—, R¹ is methyl and R² and R³ are both hydrogen orboth F, according to Scheme 10.

Reaction of Compound AI with a suitable aldehyde Compound AM (A₃, R⁶ andp are as described for compounds of Formula I) in the presence of sodiumtriacetoxyborohydride in a suitable solvent such as CH₃OH results inCompound AN, which is subsequently deprotected with TFA, for example inCH₂Cl₂, to provide the desired Compound AO.

Compound AI as prepared by the methods of Scheme 9 can be reacted in oneor two steps to provide Compound AR, e.g. a compound of Formula Iwherein L is —NH—, R¹ is methyl and R² and R³ are both hydrogen or bothF, according to Scheme 11/11a.

Reaction of Compound AI with a suitable halogenated Compound AP (A₃, R⁶and p are as described for compounds of Formula I, X is a halogen) inthe presence of potassium carbonate in a suitable solvent such asisopropanol results in Compound AQ, which is subsequently deprotectedwith TFA, for example in CH₂Cl₂, to provide the desired Compound AR.Alternatively, the reaction of Compound AI with a suitable halogenatedCompound AP (A₃, R⁶ and p are as described for compounds of Formula I, Xis a halogen) in the presence of HCl in dioxane in a suitable solventsuch as isopropanol, in addition to forming the amine linked ring A₃,results in removal of the amine protecting group to provide the desiredCompound AR in a single step 1a.

Compounds as described herein, including compositions and methods of usethereof, are illustrated further by the following examples, which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them. Analogous structures andalternative synthetic routes within the scope of the invention will beapparent to those skilled in the art.

EXAMPLES General

Reagents and solvents obtained from commercial suppliers are usedwithout further purification unless otherwise stated. Thin layerchromatography is performed on precoated 0.25 mm silica gel plates (E.Merck, silica gel 60, F₂₅₄) or similar. Visualization is achieved usingUV illumination or staining with phosphomolybdic acid, ninhydrin orother common staining reagents. Flash column chromatography is performedusing an ISCO system and prepacked silica gel columns. Preparatory HPLCis performed on a Varian Prepstar high performance liquid chromatograph.¹H NMR spectra are recorded at 400 MHz on a Bruker Avance spectrometer.Chemical shifts are reported in parts per million (ppm) downfieldrelative to tetramethylsilane (TMS) or to proton resonances resultingfrom incomplete deuteration of the NMR solvent (δ scale). Mass spectra(LCMS) are recorded on an Agilent series 1100 mass spectrometerconnected to an Agilent series 1100 HPLC. In some instances thesynthetic examples give a racemic mixture of stereoisomers, which arereadily separated by chiral HPLC.

LCMS is performed on an Agilent 1100 Series HPLC with a Series 1100 MSDwith electrospray ionization using a Phenomenex Luna C18 4.6 mm i.d.×30mm length, 3μ particle size column or similar. Compound purity istypically determined by HPLC/MS analysis using a variety of analyticalmethods.

The examples are intended to be illustrative and are not limiting orrestrictive to the scope of the invention. For example, where additionalcompounds are prepared similarly to synthetic methods of anotherexample, or in the same manner as another example, it is understood thatconditions may vary, for example, any of the solvents, reaction times,reagents, temperatures, work up conditions, or other reaction parametersmay be varied employing alternate solvents, reagents, reaction times,temperatures, work up conditions, and the like, as are readily availableto one skilled in the art.

Example 1 Synthesis of(E)-N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide(3)

(E)-N-(1-(4-Bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide3 was prepared from 1-(4-bromothiophen-2-yl)ethanone 1 and2-methylpropane-2-sulfinamide 2 in one Step as follows:

Step 1—synthesis of(E)-N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide(3)

1-(4-Bromothiophen-2-yl)ethanone (1, 4 g, 19.5 mmol),2-methylpropane-2-sulfinamide (2, 2.6 g, 21.5 mmol) andtetraethoxytitanium (9.7 g, 25.4 mmol) were combined in 100 mL of THF.The mixture was heated at 75° C. overnight, then concentrated undervacuum and the residue was dissolved in 100 mL of CH₂Cl₂. The mixturewas poured into 200 mL of ice-water and stirred for 5 minutes, thenfiltered through a celite pad and the solid was washed with 2×30 mL ofCH₂Cl₂. The organic phase was separated from the filtrate and washedwith brine, then dried, filtered and the filtrate was concentrated undervacuum. The resulting material was purified by flash columnchromatography (hexane/EtOAc). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound as a yellowsolid (3, 4.1 g, 16 mmol).

(E)-N-(1-(1-(5-Bromopyridin-3-yl)-1H-pyrazol-4-yl)ethylidene)-2-methylpropane-2-sulfinamide7 was prepared from 3-bromo-5-fluoropyridine 4 and1-(1H-pyrazol-4-yl)ethanone 5 in two Steps as follows:

Step 1a—synthesis of 1-(1-(5-bromopyridin-3-yl)-1H-pyrazol-4-yl)ethanone(6)

A mixture of 3-bromo-5-fluoropyridine (4, 1 g, 9.1 mmol),1-(1H-pyrazol-4-yl)ethanone (5, 1.6 g, 9.1 mmol) and Cs₂CO₃ (3.55 g,10.9 mmol) in 15 mL of DMF was heated at 120° C. in a microwave oven for30 minutes. The reaction was cooled to room temperature and diluted with150 mL of water and filtered. The solid was collected and dried toprovide the desired compound (6, 2 g, 7.5 mmol, 83% yield).

Step 1—synthesis of(E)-N-(1-(1-(5-bromopyridin-3-yl)-1H-pyrazol-4-yl(ethylidene)-2-methylpropane-2-sulfinamide(7)

1-(1-(5-Bromopyridin-3-yl)-1H-pyrazol-4-yl)ethanone (6) is reactedsimilarly to the above Step 1 to provide(E)-N-(1-(1-(5-bromopyridin-3-yl)-1H-pyrazol-4-yl)ethylidene)-2-methylpropane-2-sulfinamide7.

Additional sulfinamide compounds are prepared similarly to this method,optionally replacing 1-(4-bromothiophen-2-yl)ethanone 1 with a suitableethanone in Step 1, or replacing 1-(1H-pyrazol-4-yl)ethanone 5 with asuitable ethanone compound in Step 1a, and/or optionally replacing2-methylpropane-2-sulfinamide 2 with the (S) or (R) isomer thereof inStep 1. The following compounds are prepared:

-   (S,E)-N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide    (8),-   (R,E)-N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide    (9),-   (S,E)-N-(1-(5-bromo-3-chlorothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide    (10),-   (E)-N-(1-(5-bromo-3-chlorothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide    (11),-   (S,E)-N-(1-(1-(5-bromopyridin-3-yl)-1H-pyrazol-4-yl)ethylidene)-2-methylpropane-2-sulfinamide    (12),-   (S,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide-   (13),-   (E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide    (14),-   (R,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide-   (15), and-   (S,E)-N-(1-(3-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide    (16). The following table provides the compound number (column 1),    compound used in Step 1 or 1a (column 2 ethanone Step 1 unless Step    1a is indicated), sulfinamide used in Step 1 (column 3, as (S), (R),    or racemic (2)) to give the compound shown in column 4.

Comp. No. ethanone sulfinamide Compound structure  8

(S)

 9

(R)

10

(S)

11

racemic

12

  Step 1a (S)

13

(S)

14

racemic

15

(R)

16

(S)

Example 2 Synthesis of4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine(25)

4-(5-Bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine25 was prepared from 1-(5-bromo-2-fluorophenyl)ethanone 17 anddihydro-2H-pyran-4(3H)-one 18 in seven Steps as follows:

Step 1—synthesis of1-(5-bromo-2-fluorophenyl)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethanone(19)

Lithium bis(trimethylsilyl)amide (12 mL, 1M in THF, 12 mmol) was dilutedwith 12 mL of dry THF, and the solution was cooled to −78° C. for 5minutes under nitrogen. A solution of1-(5-bromo-2-fluoro-phenyl)ethanone (17, 2 g, 9.21 mmol) in 4 mL of THFwas added dropwise over 10 minutes and the mixture was stirred at −78°C. for 30 minutes. Dihydro-2H-pyran-4(3H)-one (18, 1.2 g, 12 mmol) in 2mL of THF was added dropwise and the mixture was stirred at −78° C. for15 minutes, and then gradually warmed to room temperature over 2 hours.The reaction was quenched with saturated aqueous NH₄Cl and extractedwith 2×60 mL of EtOAc. The organic portion was dried, filtered and thefiltrate concentrated under vacuum and the residue purified by flashcolumn chromatography (hexane/EtOAc 0-50%). Appropriate fractions werecombined and concentrated under vacuum to provide the desired compoundas a white solid (19, 2.1 g, 6.6 mmol).

Step 2—synthesis of1-(5-bromo-2-fluorophenyl)-2-(4-(tert-butyldimethylsilyloxy)tetrahydro-2H-pyran-4-yl)ethanone(20)

tert-Butyldimethylsilyl triflate (2.5 g, 9.46 mmol) was added to a 0° C.solution of1-(5-bromo-2-fluoro-phenyl)-2-(4-hydroxytetrahydropyran-4-yl)ethanone(19, 2.0 g, 6.31 mmol) and 2,6-lutidine (1.35 g, 12.61 mmol) in 20 mL ofCH₂Cl₂. The mixture stood at 0° C. for 2 hours, followed by 3 hours atroom temperature, then was poured into saturated aqueous NaHCO₃. Theorganic portion was separated, washed with aqueous 10% HCl, saturatedNaHCO₃, and brine, then dried with MgSO₄, filtered and the filtrateconcentrated under vacuum. The resulting material was purified by flashcolumn chromatography (hexane/EtOAc 0-40%). Appropriate fractions werecombined and concentrated under vacuum to provide the desired compound(20, 2.55 g, 5.91 mmol).

Step 3—synthesis of(Z)—N-(1-(5-bromo-2-fluorophenyl)-2-(4-(tert-butyldimethylsilyloxy)tetrahydro-2H-pyran-4-yl)ethylidene)-2-methylpropane-2-sulfinamide(21)

1-(5-Bromo-2-fluorophenyl)-2-(4-(tert-butyldimethylsilyloxy)tetrahydro-2H-pyran-4-yl)ethanone(20, 2.0 g, 4.64 mmol), 2-methylpropane-2-sulfinamide (2, 1.40 g, 11.6mmol) and tetraethoxytitanium (4.2 g, 18.54 mmol) were combined in 20 mLof dry THF and heated at refluxing for overnight. This was concentratedunder vacuum and the residue was dissolved in 100 mL of CH₂Cl₂, then themixture was poured into 100 mL of ice-water and stirred for 5 minutes.The inorganic solid was removed by filtration through a celite pad, thenthe solid was washed with 2×15 mL of CH₂Cl₂. The organic phase wasseparated from the filtrate and washed with brine, dried and filteredand the filtrate concentrated under vacuum. The resulting material waspurified by flash column chromatography (hexane/EtOAc 0-50%).Appropriate fractions were combined and concentrated under vacuum toprovide the desired compound (21, 2.4 g, 4.5 mmol).

Step 4—synthesis ofN-(2-(5-bromo-2-fluorophenyl)-1-(4-(tert-butyldimethylsilyloxy)tetrahydro-2H-pyran-4-yl)propan-2-yl)-2-methylpropane-2-sulfinamide(22)

(Z)—N-(1-(5-Bromo-2-fluorophenyl)-2-(4-(tert-butyldimethylsilyloxy)tetrahydro-2H-pyran-4-yl)ethylidene)-2-methylpropane-2-sulfinamide(21, 2.2 g, 4.1 mmol) was dissolved in 20 mL of dry THF and stirred at−20° C. under nitrogen for 5 minutes, then CH₃MgBr (4.1 mL, 3M in ether,12.3 mmol) was added dropwise. The resulting mixture was stirred at 0°C. for 1 hour. The reaction mixture was quenched with saturated aqueousNH₄Cl at 0° C., extracted with 2×80 mL of EtOAc, and the organic portionwas dried, filtered and the filtrate concentrated under vacuum. Theresulting material was purified by flash column chromatography(hexane/EtOAc 0-80%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound as a whitesolid (22, 1.1 g, 2.0 mmol).

Step 5—synthesis ofN-(2-(5-bromo-2-fluorophenyl)-1-(4-hydroxytetrahydro-2H-pyran-4-yl)propan-2-yl)-2-methylpropane-2-sulfinamide(23)

N-(2-(5-Bromo-2-fluorophenyl)-1-(4-(tert-butyldimethylsilyloxy)tetrahydro-2H-pyran-4-yl)propan-2-yl)-2-methylpropane-2-sulfinamide(22, 1.3 g, 2.4 mmol) was dissolved in 8 mL of dry THF, then 7.1 mL oftetrabutylammonium fluoride (1N in THF) was added and the mixturestirred for 3 hours at room temperature. The reaction was diluted with80 mL of EtOAc, then washed with saturated aqueous NH₄Cl, water andbrine. The organic portion was dried, filtered and the filtrateconcentrated under vacuum and the resulting material was purified byflash column chromatography (hexane/EtOAc 0-100%). Appropriate fractionswere combined and concentrated under vacuum to provide the desiredcompound as a white solid (23, 1.0 g, 2.11 mmol).

Step 6—synthesis of4-(2-amino-2-(5-bromo-2-fluorophenyl)propyl)tetrahydro-2H-pyran-4-ol(24)

N-(2-(5-Bromo-2-fluorophenyl)-1-(4-hydroxytetrahydro-2H-pyran-4-yl)propan-2-yl)-2-methylpropane-2-sulfinamide(23, 0.91 g, 2.09 mmol) was dissolved in 10 mL of dry CH₂Cl₂, and 15 mLof HCl (4N in dioxane) was added. The mixture was stirred at roomtemperature for 30 minutes, then concentrated under vacuum. The residuewas dissolved in 80 mL of EtOAc, washed with saturated aqueous NaHCO₃,and the aqueous layer was extracted with 2×20 mL of EtOAc. The combinedorganic phase was washed with brine and dried over Na₂SO₄, filtered andthe filtrate concentrated under vacuum to provide the desired compound(24, 690 mg, 2.08 mmol).

Step 7—synthesis of4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine(25)

4-(2-Amino-2-(5-bromo-2-fluorophenyl)propyl)tetrahydro-2H-pyran-4-ol(24, 690 mg, 2.05 mmol), and BrCN (435 mg, 4.1 mmol) were combined in 10mL of dry EtOH and heated at 80° C. in a sealed-tube for 24 hours. Thereaction mixture was diluted with 80 mL of EtOAc, washed with saturatedaqueous NaHCO₃, and brine. The organic portion was dried, filtered andthe filtrate concentrated under vacuum and the resulting material waspurified by flash column chromatography (hexane/EtOAc 20-100%).Appropriate fractions were combined and concentrated under vacuum toprovide the desired compound as a white solid (25, 0.3 g, 0.8 mmol).

Additional compounds are prepared following the methods of this example,wherein 1-(5-bromo-2-fluoro-phenyl)ethanone 17 is optionally replacedwith a suitable (hetero)aryl ethanone and dihydro-2H-pyran-4(3H)-one 18is optionally replaced with a suitable cyclic ketone in Step 1. Inaddition, 2-methylpropane-2-sulfinamide 2 is optionally replaced withthe (S) or (R) isomer thereof, which under suitable conditions results aspecific (S) or (R) isomer on the chiral ring carbon (e.g. the 4position of compound 25). The following compounds were prepared by thismethod:

-   8-(4-bromothiophen-2-yl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (26),-   4-(4-bromothiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (27),-   (S)-4-(4-bromothiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (28),-   (R)-4-(4-bromothiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (29),-   (S)-4-(4-bromo-5-methylthiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (30),-   4-(4-bromothiophen-2-yl)-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine    (31),-   (S)-4-(4-bromothiophen-2-yl)-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine    (32),-   (S)-8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (33),-   (R)-8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (34),-   8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (35),-   (S)-4-(5-bromo-2-fluorophenyl)-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine    (36), and-   (S)-4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (37).    The following table provides the compound number (column 1) and    compounds used in Step 1 (column 2) to give the compound shown in    column 3. An asterisk by the compound number indicates this was    prepared using (S)-2-methylpropane-2-sulfinamide in Step 3 resulting    in the (S) isomer in Step 4 as indicated in the structure of    column 3. Two asterisks similarly indicate use of    (R)-2-methylpropane-2-sulfinamide in Step 3 resulting in the (R)    isomer in Step 4.

Comp. number Step 1 reactants Structure 26

27

 28*

 29**

 30*

31

 32*

 33*

 34**

35

 36*

 37*

Example 3 Synthesis of4-(5-bromo-2-fluorophenyl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine(48)

4-(5-Bromo-2-fluorophenyl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine48 was prepared from cyclohex-1-enecarboxylic acid 38 in nine Steps asfollows:

Step 1—synthesis of cyclohexenylmethanol (39)

Cyclohex-1-enecarboxylic acid (38, 2.9 g, 23 mmol) was dissolved in 50mL of ether, then 28 mL of lithium aluminum hydride (1 M in THF, 28mmol) was added dropwise under nitrogen. The mixture was heated atrefluxing for 1 hour, then cooled to 0° C. and quenched with 4 mL ofwater, followed by 35 mL of aqueous 10% H₂SO₄. The organic phase wasseparated and the aqueous layer was extracted with 30 mL of ether. Thecombined organic portions were dried over Na₂SO₄, filtered and thefiltrate concentrated under vacuum to provide the desired compound as aliquid (39, 2.6 g, 23 mmol).

Step 2—synthesis of 1-(bromomethyl)cyclohex-1-ene (40)

Dibromo(triphenyl)-phosphane (22 g, 53 mmol) was dissolved in 120 mL ofdry CH₂Cl₂, cooled with an ice-water bath and a solution ofcyclohexenylmethanol (39, 5.5 g, 49 mmol) in 10 mL of CH₂Cl₂ was addeddropwise. The mixture was stirred at 0° C. for 3 hours, then 100 gsilica-gel was added to the mixture, concentrated under vacuum andpurified by flash column chromatography (100% hexane). Appropriatefractions were combined and concentrated under vacuum to provide thedesired compound (40, 5.7 g, 33 mmol).

Step 3—synthesis of bromo(cyclohexen-1-ylmethyl)zinc (41)

Zinc dust (1.5 g, 22.8 mmol) was suspended in 10 mL of dry THF, and1,2-dibromoethane (0.16 g, 0.85 mmol) was added to the suspension. Themixture was heated at 60° C. for 5 minutes, then cooled to roomtemperature and chloro(trimethyl)silane (0.1 g, 0.85 mmol) was added.The mixture was stirred at room temperature for 10 minutes, then asolution of 1-(bromomethyl)cyclohex-1-ene (40, 1 g, 5.7 mmol) in 2 mL ofTHF was added dropwise over 20 minutes. The resulting mixture wasstirred at room temperature for 15 hours. The zinc was removed byfiltration and the filtrate containing the desired compound 41 was usedin the next step.

Step 4—synthesis of(R)—N-(2-(5-bromo-2-fluorophenyl)-1-cyclohexenylpropan-2-yl)-2-methylpropane-2-sulfinamide(42)

A solution of(R,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide(15, 0.5 g, 1.562 mmol) was dissolved in 3 mL of THF and cooled to −30°C., then AlMe₃ (0.9369 mL, 1.874 mmol) was added and the reaction wasstirred for 30 minutes. Bromo(cyclohexen-1-ylmethyl)zinc (41, 6 mL,3.123 mmol in THF) was added slowly and the reaction was stirred at −30°C. for 1 hour, then warmed to room temperature. The reaction mixture wasdiluted with EtOAc, and the resulting solution was washed with saturatedaqueous NaHCO₃. The organic phase was dried with Na₂SO₄, filtered andthe filtrate concentrated under vacuum to give a mixture of containingthe desired compound 42. MS: 416.1 m/z (M+H)⁺.

Step 5—synthesis of2-(5-bromo-2-fluorophenyl)-1-cyclohexenylpropan-2-amine (43)

(R)—N-(2-(5-Bromo-2-fluorophenyl)-1-cyclohexenylpropan-2-yl)-2-methylpropane-2-sulfinamide(42, 0.62 g, 1.489 mmol) was dissolved in 3 mL of MeOH and 3 mL of HCl(4N in dioxane) was added. The reaction was stirred at room temperaturefor 2 hours, then concentrated under vacuum and the residue re-dissolvedin EtOAc. The resulting solution was washed with saturated aqueousNaHCO₃, and the organic phase was dried with Na₂SO₄, filtered and thefiltrate concentrated under vacuum. The resulting material was purifiedby silica gel chromatography (ISCO, hexane/EtOAc 0-100%). Appropriatefractions were combined and concentrated under vacuum to provide thedesired compound (43, 0.189 g, 0.6054 mmol, 40.66%). MS: 312.1 m/z(M+H)⁺.

Step 6—synthesis ofN-(2-(5-bromo-2-fluorophenyl)-1-cyclohexenylpropan-2-ylcarbamothioyl)benzamide(45)

2-(5-Bromo-2-fluorophenyl)-1-cyclohexenylpropan-2-amine (43, 0.185 g,0.5926 mmol) was dissolved in THF and benzoyl isothiocyanate (44,0.08704 g, 0.5333 mmol) was added. The reaction was stirred at roomtemperature for 1 hour, then concentrated under vacuum. The resultingmaterial was purified by silica gel chromatography (ISCO, hexane/EtOAc0-50%). Appropriate fractions were combined and concentrated undervacuum to provide the desired compound (45, 0.271 g, 0.5700 mmol,96.20%). MS: 475.1 m/z (M+H)⁺.

Step 7—synthesis ofN-(4-(5-bromo-2-fluorophenyl)-7-iodo-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-yl)benzamide(46)

Iodine (0.2883 g, 1.136 mmol) was added to a solution ofN-(2-(5-bromo-2-fluorophenyl)-1-cyclohexenylpropan-2-ylcarbamothioyl)benzamide(45, 0.27 g, 0.5679 mmol) in 2 mL of THF and the resulting solution wasstirred at room temperature for 3 hours. The reaction was diluted withEtOAc and washed with 1 N aqueous Na₂SO₃. The organic phase was driedwith Na₂SO₄, filtered and the filtrate concentrated under vacuum. Theresulting material was purified by silica gel chromatography (ISCO,hexane/EtOAc 0-50%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound (46, 0.32 g,0.5322 mmol, 93.70%). MS: 600.9 m/z (M+H)⁺.

Step 8—synthesis ofN-(4-(5-bromo-2-fluorophenyl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-yl)benzamide(47)

Sodium cyanoborohydride (0.09144 g, 1.455 mmol) was added to a solutionofN-(4-(5-bromo-2-fluorophenyl)-7-iodo-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-yl)benzamide(46, 0.175 g, 0.2910 mmol) in 3 mL of MeOH and HOAc (0.03495 g, 0.5821mmol) and the resulting mixture was stirred at room temperature for 18hours. A further addition of sodium cyanoborohydride (0.09144 g, 1.455mmol) was made and the reaction was stirred for another 6 hours. Themixture was concentrated under vacuum and the residue was re-dissolvedin EtOAc and washed with saturated NaHCO₃. The organic phase was driedwith Na₂SO₄, filtered and the filtrate concentrated under vacuum. Theresulting material was purified by silica gel chromatography (ISCO,hexane/EtOAc 0-100%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound (47, 0.105 g,0.2209 mmol, 75.89%). MS: 475.0 m/z (M+H)⁺.

Step 9—synthesis of4-(5-bromo-2-fluorophenyl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine(48)

Hydrazine (0.1416 g, 4.417 mmol) was added to a solution ofN-(4-(5-bromo-2-fluorophenyl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-yl)benzamide(47, 0.105 g, 0.2209 mmol) in 1 mL of of CH₂Cl₂ and the resultingsolution was stirred at room temperature for 18 hours. The mixture wasdiluted with CH₂Cl₂ and washed with brine. The organic phase was driedwith Na₂SO₄, filtered and the filtrate concentrated under vacuum. Theresulting material was purified by silica gel chromatography (ISCO,hexane/EtOAc 0-100%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound (48, 0.08 g,0.2155 mmol, 97.55%). MS: 371.0 m/z (M+H)⁺.

Additional compounds are prepared following the methods of this example,wherein cyclohex-1-enecarboxylic acid 38 is optionally replaced withcyclobut-1-enecarboxylic acid in Step 1 and(R,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide15 is optionally replaced with a suitable sulfinamide in Step 4. Whenthe (S) or (R) isomer of the sulfonamide compound is used under suitableconditions, Step 5 results in the (S) or (R) isomer on the chiral ringcarbon (e.g. the 4 position of compound 48). The following compoundswere prepared by this method:

-   (R)-8-(5-bromo-2-fluorophenyl)-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-6-amine    (49),-   (S)-8-(5-bromo-2-fluorophenyl)-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-6-amine    (50),-   (4S)-4-(3-bromothiophen-2-yl)-7,7,8,8,9,9,10,10,11-nonadeutero-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (51), and-   (S)-4-(5-bromo-2-fluorophenyl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (52).    The following table provides the compound number (column 1),    compound used in Step 1 (column 2), and compound used in Step 4    (column 3) to give the compound shown in column 4.

Comp. number Step 1 Step 2 Structure 49

50

51

52

Example 4 Synthesis of8-(4-bromothiophen-2-yl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine(63)

8-(4-Bromothiophen-2-yl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine63 was prepared from 2-methylenepropane-1,3-diol 53 in nine Steps asfollows:

Step 1—synthesis of 2-((tert-butyldiphenylsilyloxy)methyl)prop-2-en-1-ol(54)

2-Methylenepropane-1,3-diol (53, 5 g, 56.75 mmol) was dissolved in 100mL of CH₂Cl₂ and the resulting solution was cooled to 0° C. Imidazole(7.728 g, 113.5 mmol) was added followed bytert-butyl-chloro-diphenyl-silane (14.04 g, 13.07 mL, 51.08 mmol) andthe resulting solution was stirred at room temperature for 18 hours. Thereaction mixture was washed with water and the organic phase was driedwith Na₂SO₄, filtered and the filtrate concentrated under vacuum. Theresulting material was purified by silica gel chromatography(hexane/EtOAc 0-100%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound (54, 5.62 g,17.2 mmol, 30.3%). MS: 349.1 m/z (M+Na)⁺.

Step 2—synthesis of (2-(bromomethyl)allyloxy)(tert-butyl)diphenylsilane(55)

2-((tert-Butyldiphenylsilyloxy)methyl)prop-2-en-1-ol (54, 2.1 g, 6.4mmol) was dissolved in 20 mL of CH₂Cl₂ and the resulting solution wascooled to 0° C. Triphenylphosphine dibromide (3.3 g, 7.7 mmol) was addedand the resulting reaction was stirred for 2 hours after which thereaction mixture was washed with saturated aqueous NaHCO₃. The organicphase was dried with Na₂SO₄, filtered and the filtrate concentratedunder vacuum. The resulting material was purified by silica gelchromatography (hexane). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound (55, 2.3 g,5.9 mmol, 92%).

Step 3—synthesis ofbromo-[2-[[tert-butyl(diphenyl)silyl]oxymethyl]allyl]zinc (56)

Zinc (1.4 g, 22 mmol) was suspended in 5 mL of THF and 1,2-dibromoethane(0.15 g, 0.070 mL, 0.81 mmol) was added. The mixture was heated to 60°C. for 10 minutes then cooled to room temperature.Chloro(trimethyl)silane (0.088 g, 0.10 mL, 0.81 mmol) was added and themixture was stirred at room temperature for 15 minutes. A solution of(2-(bromomethyl)allyloxy)(tert-butyl)diphenylsilane (55, 2.1 g, 5.4mmol) in 5 mL of THF was added dropwise over 15 minutes and theresulting mixture was stirred at room temperature for 4 hours to give a0.5 M solution of the desired compound 56.

Step 4—synthesis ofN-(2-(4-bromothiophen-2-yl)-4-((tert-butyldiphenylsilyloxy)methyl)pent-4-en-2-yl)-2-methylpropane-2-sulfinamide(57)

(E)-N-(1-(4-Bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide(3, 0.12 g, 0.3892 mmol) was dissolved in 1 mL of THF and the resultingsolution was cooled to −30° C. Trimethylaluminum (0.2335 mL, in toluene0.4670 mmol) was added slowly and the resulting solution was stirred at−30° C. for 15 minutes.Bromo-[2-[[tert-butyl(diphenyl)silyl]oxymethyl]allyl]zinc (56, 2 mL,0.7785 mmol) in THF was added slowly and resulting solution was stirredat −30° C. for 1 hour and then warmed to room temperature. Afterstirring at room temperature for 1 hour, the reaction was diluted withEtOAc and washed with saturated aqueous NaHCO₃. The organic phase wasdried with Na₂SO₄, filtered and the filtrate concentrated under vacuumand the residue was purified by silica gel chromatography (hexane/EtOAc0-100%). Appropriate fractions were combined and concentrated undervacuum to provide the desired compound (57, 0.192 g, 0.3103 mmol,79.72%). MS: 640.1 m/z (M+Na)⁺.

Step 5—synthesis of4-amino-4-(4-bromothiophen-2-yl)-2-methylenepentan-1-ol (58)

HCl (10 mL, 40 mmol, 4 N in dioxane) was added to a solution ofN-(2-(4-bromothiophen-2-yl)-4-((tert-butyldiphenylsilyloxy)methyl)pent-4-en-2-yl)-2-methylpropane-2-sulfinamide(57, 2.42 g, 3.91 mmol) in 10 mL of MeOH and the resulting solution wasstirred at room temperature for 2 hours. The solution was diluted withCH₂Cl₂ and washed with saturated aqueous NaHCO₃. The organic phase wasdried with Na₂SO₄, filtered and the filtrate concentrated under vacuumto provide the desired compound (58, 0.696 g, 2.520 mmol, 64.4%). MS:258.9 m/z (M-NH₂)⁺.

Step 6—synthesis of 9H-fluoren-9-ylmethylN-[[1-(4-bromo-2-thienyl)-3-(hydroxymethyl)-1-methyl-but-3-enyl]carbamothioyl]carbamate(60)

O-(9H-fluoren-9-yl)methyl carbonisothiocyanatidate (59, 0.7028 g, 2.4983mmol) was added to a solution of4-amino-4-(4-bromothiophen-2-yl)-2-methylenepentan-1-ol (58, 0.69 g,2.4983 mmol) in 5 mL of THF and the resulting solution was stirred atroom temperature for 1 hour. The reaction mixture was diluted with EtOAcand washed with water. The organic phase was dried with Na₂SO₄, filteredand the filtrate concentrated under vacuum. The resulting material waspurified by silica gel chromatography (hexane/EtOAc 0-100%). Appropriatefractions were combined and concentrated under vacuum to provide thedesired compound (60, 0.725 g, 1.300 mmol, 52.05%). MS: 578.9 m/z(M+Na)⁺.

Step 7—synthesis of (9H-fluoren-9-yl)methyl4-(4-bromothiophen-2-yl)-6-(hydroxymethyl)-6-(iodomethyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate(61)

Iodine (0.3770 g, 1.485 mmol) was added to a solution of9H-fluoren-9-ylmethylN-[[1-(4-bromo-2-thienyl)-3-(hydroxymethyl)-1-methyl-but-3-enyl]carbamothioyl]carbamate(60, 0.69 g, 1.238 mmol) in 6 mL of THF and the resulting solution wasstirred at room temperature for 4 hours. The reaction mixture wasdiluted with EtOAc and washed with 1N aqueous Na₂SO₃. The organic phasewas dried with Na₂SO₄, filtered and the filtrate concentrated undervacuum and the residue was purified by silica gel chromatography(hexane/EtOAc 0-100%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound (61, 0.652 g,0.9541 mmol, 77.08%). MS: 683.9 ink (M+H)⁺.

Step 8—synthesis of (9H-fluoren-9-yl)methyl8-(4-bromothiophen-2-yl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-ylcarbamate(62)

Potassium carbonate (0.08899 g, 0.6438 mmol) was added to a solution of(9H-fluoren-9-yl)methyl4-(4-bromothiophen-2-yl)-6-(hydroxymethyl)-6-(iodomethyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate(61, 0.22 g, 0.3219 mmol) in 2 mL of dioxane and 0.2 mL of water and theresulting solution was stirred at room temperature for 18 hours. Thereaction mixture was diluted with EtOAc and washed with water. Theorganic phase was dried with Na₂SO₄, filtered and the filtrateconcentrated under vacuum to give the desired compound (62, 0.152 g,0.2736 mmol, 85.00%). MS: 555.1 m/z (M+H)⁺.

Step 9—synthesis of8-(4-bromothiophen-2-yl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine(63)

(9H-fluoren-9-yl)methyl8-(4-bromothiophen-2-yl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-ylcarbamate(62, 0.12 g, 0.2160 mmol) was dissolved in CH₂Cl₂ and piperidine(0.09197 g, 1.080 mmol) was added. The reaction mixture was stirred atroom temperature for 4 hours, then concentrated under vacuum and theresidue purified by silica gel chromatography (hexane/EtOAc 0-100%).Appropriate fractions were combined and concentrated under vacuum andthe resulting material was further purified by HPLC. Appropriatefractions were combined and concentrated under vacuum to give thedesired compound (63, 0.025 g, 0.07501 mmol, 34.72%). MS: 333.0 m/z(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ: 7.44 (d, J=1.4 Hz, 1H), 7.11 (d,J=1.4 Hz, 1H), 3.71 (d, J=10.3 Hz, 1H), 3.35 (m, 3H), 2.55 (s, 2H), 1.79(s, 3H).

(S)-8-(5-bromo-2-fluorophenyl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine64,

was prepared by this method, replacing(E)-N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide3 with(S,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide13 in Step 4.

Example 5 Synthesis of4-(5-bromo-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine(71)

4-(5-Bromo-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine71 was prepared from1-(5-bromo-2-fluorophenyl)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethanone19 (prepared as described in Example 2) and(4-methoxyphenyl)methanethiol 65 in six Steps as follows:

Step 1—synthesis of1-(5-bromo-2-fluorophenyl)-2-(4-(4-methoxybenzylthio)tetrahydro-2H-pyran-4-yl)ethanone(66)

1-(5-Bromo-2-fluorophenyl)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethanone(19, 550 mg, 1.73 mmol) and (4-methoxyphenyl)methanethiol (65, 802 mg,5.2 mmol) were combined in 10 mL of dry CH₃NO₂, and dibromocopper (39mg, 0.17 mmol) was added. The resulting mixture was sonicated withAquasonic (Model 50D) for 5 minutes. The reaction mixture wasconcentrated under vacuum and the residue was purified by flash columnchromatography (hexane/EtOAc 0-20%). Appropriate fractions were combinedand concentrated under vacuum to provide the desired compound (66, 770mg, 1.70 mmol).

Step 2—synthesis of(Z)—N-(1-(5-bromo-2-fluorophenyl)-2-(4-(4-methoxybenzylthio)tetrahydro-2H-pyran-4-yl)ethylidene)-2-methylpropane-2-sulfinamide(67)

1-(5-Bromo-2-fluorophenyl)-2-(4-(4-methoxybenzylthio)tetrahydro-2H-pyran-4-yl)ethanone(66, 800 mg, 1.76 mmol), 2-methylpropane-2-sulfinamide (2, 535 mg, 4.41mmol) and tetraethoxytitanium (2.4 g, 10.6 mmol) were combined in 12 mLof dry THF and heated at refluxing for overnight. The reaction wasconcentrated under vacuum and the residue dissolved in 150 mL of CH₂Cl₂,then the mixture was poured into 50 mL of ice-water and stirred for 5minutes. The inorganic solid was removed by filtration through a celitepad, then the solid was washed with 2×15 mL of CH₂Cl₂. The organic phasewas separated from the filtrate and washed with brine, dried andfiltered and the filtrate concentrated under vacuum. The resultingmaterial was purified by flash column chromatography (hexane/EtOAc0-50%). Appropriate fractions were combined and concentrated undervacuum to provide the desired compound (67, 870 mg, 1.56 mmol).

Step 3—synthesis ofN-(2-(5-bromo-2-fluorophenyl)-1-(4-(4-methoxybenzylthio)tetrahydro-2H-pyran-4-yl)propan-2-yl)-2-methylpropane-2-sulfinamide(68)

(Z)—N-(1-(5-Bromo-2-fluorophenyl)-2-(4-(4-methoxybenzylthio)tetrahydro-2H-pyran-4-yl)ethylidene)-2-methylpropane-2-sulfinamide(67, 1.1 g, 1.98 mmol) was dissolved in 20 mL of dry THF and stirred at−20° C. under nitrogen for 5 minutes, then CH₃MgBr (5.27 mL, 3M inether, 15.8 mmol) was added dropwise. The resulting mixture was stirredat −20° C. for 1 hour. The reaction mixture was quenched with saturatedaqueous NH₄Cl at 0° C., extracted with 2×80 mL of EtOAc, and the organicportion was dried, filtered and the filtrate concentrated under vacuum.The resulting material was purified by flash column chromatography(hexane/EtOAc 0-80%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound as an oil (68,335 mg, 0.58 mmol).

Step 4—synthesis of2-(5-bromo-2-fluorophenyl)-1-(4-(4-methoxybenzylthio)tetrahydro-2H-pyran-4-yl)propan-2-amine(69)

N-(2-(5-Bromo-2-fluorophenyl)-1-(4-(4-methoxybenzylthio)tetrahydro-2H-pyran-4-yl)propan-2-yl)-2-methylpropane-2-sulfinamide(68, 335 mg, 0.58 mmol) was dissolved in 3 mL of dry CH₂Cl₂, and 1 mL ofHCl (4N in dioxane) was added. The mixture was stirred at roomtemperature for 30 minutes, then concentrated under vacuum. The residuewas dissolved in 50 mL of EtOAc, washed with saturated aqueous NaHCO₃,and the aqueous layer was extracted with 2×20 mL of EtOAc. The combinedorganic phase was washed with brine and dried over Na₂SO₄, filtered andthe filtrate concentrated under vacuum to provide the desired compound(69, 270 mg, 0.57 mmol).

Step 5—synthesis of4-(2-amino-2-(5-bromo-2-fluorophenyl)propyl)tetrahydro-2H-pyran-4-thiol(70)

2-(5-Bromo-2-fluorophenyl)-1-(4-(4-methoxybenzylthio)tetrahydro-2H-pyran-4-yl)propan-2-amine(69, 270 mg, 0.57 mmol) and anisole (187 mg, 1.73 mmol) were combined in6 mL TFA and heated at 90° C. in a sealed tube for 3 hours. The reactionmixture was concentrated under vacuum and the resulting material waspurified by HPLC (acetonitrile/water with 0.1% TFA). Appropriatefractions were combined and concentrated under vacuum to provide thedesired compound as a TFA salt (70, 220 mg, 0.47 mmol).

Step 6—synthesis of4-(5-bromo-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine(71)

4-(2-amino-2-(5-bromo-2-fluorophenyl)propyl)tetrahydro-2H-pyran-4-thiol(70, 90 mg, 0.26 mmol), BrCN (27.5 mg, 0.26 mmol), andN-ethyl-N-isopropyl-propan-2-amine (40 mg, 0.31 mmol) were combined in 2mL of dry EtOH and flushed with nitrogen. The mixture was stirred atroom temperature for 1 hour, then heated at 75° C. in a sealed tube for6 hours. The reaction mixture was diluted with 25 mL of EtOAc, washedwith saturated aqueous NaHCO₃, and brine and the organic portion wasdried, filtered and the filtrate concentrated under vacuum. Theresulting material was purified by flash column chromatography(hexane/EtOAc 20-100%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound as a whitesolid (71, 70 mg, 0.18 mmol).

4-(4-bromothiophen-2-yl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine72,

was prepared following the methods of this example, where1-(5-bromo-2-fluorophenyl)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethanone19 is replaced with1-(4-bromothiophen-2-yl)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethanone(prepared by the methods of Example 2, isolated after Step 1 in thepreparation of4-(4-bromothiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine27.

(S)-4-(5-bromo-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine73, and(R)-4-(5-bromo-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine74

were prepared following the methods of this example, where2-methylpropane-2-sulfinamide 2 is replaced with either the (S) or (R)isomer thereof in Step 2, respectively, resulting in the (S) or (R)isomer, respectively, on the chiral carbon generated in step 3.

Example 6 Synthesis of(S)-7-(5-bromo-2-fluorophenyl)-7-methyl-4-oxa-6-azaspiro[2.5]oct-5-en-5-amine(86)

(S)-7-(5-bromo-2-fluorophenyl)-7-methyl-4-oxa-6-azaspiro[2.5]oct-5-en-5-amine86 was prepared from ethyl 3-(5-bromo-2-fluorophenyl)-3-oxopropanoate 75and ethane-1,2-diol 76 in nine Steps as follows:

Step 1—synthesis of ethyl2-(2-(5-bromo-2-fluorophenyl)-1,3-dioxolan-2-yl)acetate (77)

Ethyl 3-(5-bromo-2-fluorophenyl)-3-oxopropanoate (75, 6 g, 20.75 mmol)was dissolved in 100 mL of toluene, then ethane-1,2-diol (76, 7.72 g,124.2 mmol) and p-toluenesulfonic acid (285 mg, 1.66 mmol) were added.The resulting mixture was heated at refluxing by using Dean-Starkapparatus to remove water. After 5 hours, the reaction mixture wasdiluted with 100 mL of EtOAc, washed with saturated aqueous NaHCO₃,water and brine. The organic portion was dried, filtered and thefiltrate concentrated under vacuum and the residue purified by flashcolumn chromatography (hexane/EtOAc 0-25%). Appropriate fractions werecombined and concentrated under vacuum to provide the desired compoundas an oil (77, 1.9 g, 5.1 mmol).

Step 2—synthesis of1-((2-(5-bromo-2-fluorophenyl)-1,3-dioxolan-2-yl)methyl)cyclopropanol(78)

Ethyl 2-(2-(5-bromo-2-fluorophenyl)-1,3-dioxolan-2-yl)acetate (77, 1.65g, 4.95 mmol) was dissolved in 30 mL of THF and 10 mL of Et₂O, andtetraisopropoxytitanium (0.42 g, 1.49 mmol) was added. The mixture wasstirred at 10° C. for 5 minutes, then CH₃CH₂MgBr (5 mL, 3M in ether,14.9 mmol) was added dropwise over 25 minutes and the resulting mixturewas stirred at room temperature for 3 hours. The reaction mixture wasquenched with saturated aqueous NH₄Cl at 0° C., extracted with 2×50 mLof EtOAc, and the organic portion was dried, filtered and the filtrateconcentrated under vacuum. The resulting material was purified by flashcolumn chromatography (hexane/EtOAc 0-40%). Appropriate fractions werecombined and concentrated under vacuum to provide the desired compoundas a white solid (78, 1.45 g, 4.57 mmol).

Step 3—synthesis of1-(5-bromo-2-fluorophenyl)-2-(1-hydroxycyclopropyl)ethanone (79)

1-((2-(5-Bromo-2-fluorophenyl)-1,3-dioxolan-2-yl)methyl)cyclopropanol(78, 1.45 g, 4.57 mmol) was dissolved in 40 mL of MeOH, and 1.5 mL ofconcentrated HCl was added. The mixture was stirred at room temperaturefor 24 hours. The reaction mixture was diluted with 150 mL of EtOAc,washed with 2×80 mL of water and brine, and the organic portion wasdried, filtered and the filtrate concentrated under vacuum provide thedesired compound as a white solid (79, 1.18 g, 4.32 mmol).

Step 4—synthesis of1-(5-bromo-2-fluorophenyl)-2-(1-(tert-butyldimethylsilyloxy)cyclopropyl)ethanone(80)

tert-Butyldimethylsilyl triflate (1.34 g, 5.21 mmol) was added to a 0°C. solution of1-(5-bromo-2-fluorophenyl)-2-(1-hydroxycyclopropyl)ethanone (79, 0.95 g,3.48 mmol) and 2,6-lutidine (0.75 g, 7.0 mmol) in 15 mL of CH₂Cl₂. Themixture stood at 0° C. for 2 hour, followed by 3 hours at roomtemperature, then was poured into saturated aqueous NaHCO₃. The organicportion was separated, washed with aqueous 10% HCl, saturated NaHCO₃,and brine, then dried with MgSO₄, filtered and the filtrate concentratedunder vacuum. The resulting material was purified by flash columnchromatography (hexane/EtOAc 0-40%). Appropriate fractions were combinedand concentrated under vacuum to provide the desired compound (80, 1.3g, 3.4 mmol).

Step 5—synthesis of(R,Z)—N-(1-(5-bromo-2-fluorophenyl)-2-(1-(tert-butyldimethylsilyloxy)cyclopropyl)ethylidene)-2-methylpropane-2-sulfinamide(82)

1-(5-Bromo-2-fluorophenyl)-2-(1-(tert-butyldimethylsilyloxy)cyclopropyl)ethanone(80, 1.3 g, 3.4 mmol), (R)-2-methylpropane-2-sulfinamide (81, 1.2 g, 10mmol) and tetraethoxytitanium (3.1 g, 13 mmol) were combined in 12 mL ofdry THF and heated at refluxing for overnight. This was concentratedunder vacuum and the residue was dissolved in 100 mL of CH₂Cl₂, then themixture was poured into 100 mL of ice-water and stirred for 5 minutes.The inorganic solid was removed by filtration through a celite pad, thenthe solid was washed with 2×15 mL of CH₂Cl₂. The organic phase wasseparated from the filtrate and washed with brine, dried and filteredand the filtrate concentrated under vacuum. The resulting material waspurified by flash column chromatography (hexane/EtOAc 0-50%).Appropriate fractions were combined and concentrated under vacuum toprovide the desired compound (82, 1.4 g, 2.9 mmol).

Step 6—synthesis of(R)—N—((S)-2-(5-bromo-2-fluorophenyl)-1-(1-(tert-butyldimethylsilyloxy)cyclopropyl)propan-2-yl)-2-methylpropane-2-sulfinamide(83)

(R,Z)—N-(1-(5-Bromo-2-fluorophenyl)-2-(1-(tert-butyldimethylsilyloxy)cyclopropyl)ethylidene)-2-methylpropane-2-sulfinamide(82, 1.39 g, 2.83 mmol) was dissolved in 20 mL of dry THF and stirred at−20° C. under nitrogen for 5 minutes, then MeLi (2.3 mL, 1.6 M in ether,3.68 mmol) was added dropwise. The resulting mixture was stirred at −20°C. for 1 hour. The reaction mixture was quenched with saturated aqueousNH₄Cl at 0° C., extracted with 2×80 mL of EtOAc, and the organic portionwas dried, filtered and the filtrate concentrated under vacuum. Theresulting material was purified by flash column chromatography(hexane/EtOAc 0-80%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound as a whitesolid (83, 0.25 g, 0.49 mmol).

Step 7—synthesis of(R)—N—((S)-2-(5-bromo-2-fluorophenyl)-1-(1-hydroxycyclopropyl)propan-2-yl)-2-methylpropane-2-sulfinamide(84)

(R)—N—((S)-2-(5-Bromo-2-fluorophenyl)-1-(1-(tert-butyldimethylsilyloxy)cyclopropyl)propan-2-yl)-2-methylpropane-2-sulfinamide(83, 0.25 g, 0.49 mmol) was dissolved in 3 mL of dry THF, then 1.5 mL oftetrabutylammonium fluoride (1N in THF) was added and the mixturestirred for 3 hours at room temperature. The reaction was diluted with50 mL of EtOAc, then washed with saturated aqueous NH₄Cl, water andbrine, and the organic portion was dried, filtered and the filtrateconcentrated under vacuum. The resulting material was purified by flashcolumn chromatography (hexane/EtOAc 0-100%). Appropriate fractions werecombined and concentrated under vacuum to provide the desired compoundas a white solid (84, 0.15 g, 0.38 mmol).

Step 8—synthesis of(S)-1-(2-amino-2-(5-bromo-2-fluorophenyl)propyl)cyclopropanol (85)

(R)—N—((S)-2-(5-Bromo-2-fluorophenyl)-1-(1-hydroxycyclopropyl)propan-2-yl)-2-methylpropane-2-sulfinamide(84, 0.15 g, 0.38 mmol) was dissolved in 4 mL of dry CH₂Cl₂, and 2 mL ofHCl (4N in dioxane) was added. The mixture was stirred at roomtemperature for 30 minutes, then concentrated under vacuum. The residuewas dissolved in 40 mL of EtOAc, washed with saturated aqueous NaHCO₃,and the aqueous layer was extracted with 2×10 mL of EtOAc. The combinedorganic phase was washed with brine and dried over Na₂SO₄, filtered andthe filtrate concentrated under vacuum to provide the desired compound(85, 0.11 g, 0.38 mmol).

Step 9—synthesis of(S)-7-(5-bromo-2-fluorophenyl)-7-methyl-4-oxa-6-azaspiro[2.5]oct-5-en-5-amine(86)

(S)-1-(2-Amino-2-(5-bromo-2-fluorophenyl)propyl)cyclopropanol (85, 170mg, 0.59 mmol), and BrCN (94 mg, 0.88 mmol) were combined in 5 mL of dryEtOH and heated at 60° C. in a sealed-tube for 24 hours. The reactionmixture was diluted with 50 mL of EtOAc, washed with saturated aqueousNaHCO₃, and brine and the organic portion was dried, filtered and thefiltrate concentrated under vacuum. The resulting material was purifiedby flash column chromatography (hexane/EtOAc 20-100%). Appropriatefractions were combined and concentrated under vacuum to provide thedesired compound as a white solid (86, 93 mg, 0.30 mmol).

Example 7 Synthesis of4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine(94)

4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine94 was prepared from 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone87 in seven Steps as follows:

Step 1—synthesis of(2,2-difluoro-1-(2-fluoro-5-(trimethylsilyl)phenyl)vinyloxy)trimethylsilane(88)

To a dry flask with 15 mL of dry THF, magnesium turning (0.4 g, 17 mmol)and chloro(trimethyl)silane (2.4 g, 22 mmol), were added and cooled downto 0° C. 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (87, 1.5 g,22 mmol) was added dropwise. After addition, the mixture was stirred foradditional 2 hours at 0° C. The reaction was concentrated under vacuum,and the residue was suspended in 20 mL of dry CH₂Cl₂, and insolublesolid was removed with filtration through a celite pad. The filtratesolution containing compound 88 was used in the next step.

Step 2—synthesis of2,2-difluoro-1-(2-fluoro-5-(trimethylsilyl)phenyl)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethanone(89)

Tetrachlorotitanium (0.79 g, 4.1 mmol) was dissolved in 10 mL of dryCH₂Cl₂, then cooled to −78° C. under nitrogen. A solution ofdihydro-2H-pyran-4(3H)-one (18, 0.83 g, 8.3 mmol) in 5 mL of dry CH₂Cl₂was added dropwise. The mixture was stirred at −78° C. for 15 minutes,then a solution of(2,2-difluoro-1-(2-fluoro-5-(trimethylsilyl)phenyl)vinyloxy)trimethylsilane(88, 1.1 g, 3.5 mmol) in 15 mL CH₂Cl₂ was added dropwise. The resultingmixture was stirred at −78° C. for 4 hours, then at room temperatureovernight. The reaction was quenched with 30 mL saturated NH₄Cl,extracted with 100 mL CH₂Cl₂, and the organic portion was dried,filtered and the filtrate concentrated under vacuum. The resultingmaterial was purified by flash column chromatography (hexane/EtOAc0-25%). Appropriate fractions were combined and concentrated undervacuum to provide the desired compound as a white solid (89, 0.48 g,1.38 mmol).

Step 3—synthesis of1-(5-bromo-2-fluorophenyl)-2,2-difluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethanone(90)

2,2-Difluoro-1-(2-fluoro-5-(trimethylsilyl)phenyl)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethanone(89, 0.45 g, 1.31 mmol) was dissolved in 8 mL of HOAc and 3 mL of MeOHand KBr (0.31 g, 2.62 mmol) was added. The mixture was stirred at 60° C.for 20 minutes, then 1-chloropyrrolidine-2,5-dione (0.28 g, 2.1 mmol)was added. The resulting mixture was stirred at 60° C. 15 hours. Thereaction mixture was diluted with 60 mL of EtOAc, washed with 3×30 mLwater and brine, and the organic portion was dried, filtered and thefiltrate concentrated under vacuum. The resulting material was purifiedby flash column chromatography (hexane/EtOAc 0-40%). Appropriatefractions were combined and concentrated under vacuum to provide thedesired compound as a white solid (90, 0.41 g, 1.16 mmol).

Step 4—synthesis of(E)-N-(1-(5-bromo-2-fluorophenyl)-2,2-difluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethylidene)-2-methylpropane-2-sulfinamide(91)

1-(5-Bromo-2-fluorophenyl)-2,2-difluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethanone(90, 0.35, 0.99 mmol), 2-methylpropane-2-sulfinamide (2, 0.3 g, 2.48mmol) and tetraethoxytitanium (1.14 g, 5.0 mmol) were combined in 8 mLof dry THF and heated at refluxing for overnight. This was concentratedunder vacuum and the residue was dissolved in 50 mL of CH₂Cl₂, then themixture was poured into 40 mL of ice-water and stirred for 5 minutes.The inorganic solid was removed by filtration through a celite pad, thenthe solid was washed with 2×20 mL of CH₂Cl₂. The organic phase wasseparated from the filtrate and washed with brine, dried and filteredand the filtrate concentrated under vacuum. The resulting material waspurified by flash column chromatography (hexane/EtOAc 0-50%).Appropriate fractions were combined and concentrated under vacuum toprovide the desired compound (91, 0.304 g, 0.66 mmol).

Step 5—synthesis ofN-(2-(5-bromo-2-fluorophenyl)-1,1-difluoro-1-(4-hydroxytetrahydro-2H-pyran-4-yl)propan-2-yl)-2-methylpropane-2-sulfinamide(92)

(E)-N-(1-(5-Bromo-2-fluorophenyl)-2,2-difluoro-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethylidene)-2-methylpropane-2-sulfinamide(91, 0.304 g, 0.66 mmol) was dissolved in 10 mL of dry THF and stirredat 0° C. under nitrogen for 5 minutes, then CH₃MgBr (1.1 mL, 3M inether, 3.3 mmol) was added dropwise. The resulting mixture was stirredat 0° C. for 2 hour. The reaction mixture was quenched with saturatedaqueous NH₄Cl at 0° C., extracted with 2×50 mL of EtOAc, and the organicportion was dried, filtered and the filtrate concentrated under vacuum.The resulting material was purified by flash column chromatography(hexane/EtOAc 0-80%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound as a whitesolid (92, 0.25 g, 0.53 mmol).

Step 6—synthesis of4-(2-amino-2-(5-bromo-2-fluorophenyl)-1,1-difluoropropyl)tetrahydro-2H-pyran-4-ol(93)

N-(2-(5-Bromo-2-fluorophenyl)-1,1-difluoro-1-(4-hydroxytetrahydro-2H-pyran-4-yl)propan-2-yl)-2-methylpropane-2-sulfinamide(92, 0.25 g, 0.53 mmol) was dissolved in 2 mL of dry CH₂Cl₂, and 2 mL ofHCl (4N in dioxane) was added. The mixture was stirred at roomtemperature for 30 minutes, then concentrated under vacuum. The residuewas dissolved in 50 mL of EtOAc, washed with saturated aqueous NaHCO₃,and the aqueous layer was extracted with 2×20 mL of EtOAc. The combinedorganic phase was washed with brine and dried over Na₂SO₄, filtered andthe filtrate concentrated under vacuum to provide the desired compound(93, 0.18 g, 0.51 mmol).

Step 7—synthesis of4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine(94)

4-(2-Amino-2-(5-bromo-2-fluorophenyl)-1,1-difluoropropyl)tetrahydro-2H-pyran-4-ol(93, 190 mg, 0.516 mmol), and BrCN (164 mg, 1.55 mmol) were combined in6 mL of dry EtOH and heated at 80° C. in a sealed-tube for 24 hours. Thereaction mixture was diluted with 50 mL of EtOAc, washed with saturatedaqueous NaHCO₃, and brine and the organic portion was dried, filteredand the filtrate concentrated under vacuum. The resulting material waspurified by flash column chromatography (hexane/EtOAc 20-100%).Appropriate fractions were combined and concentrated under vacuum toprovide the desired compound as a white solid (94, 118 g, 0.3 mmol).

Additional compounds are prepared following the methods of this example,wherein 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone 87 isoptionally replaced with a suitable trifluoroethanone in Step 1 anddihydro-2H-pyran-4(3H)-one 18 is optionally replaced with a suitablecyclic ketone in Step 2. The (S) or (R) isomer of the2-methylpropane-2-sulfinamide 2 is optionally used in Step 4, with theresult that Step 5 provides a specific (S) or (R) isomer ultimatelyproviding a specific isomer of the chiral ring carbon (e.g. the 4position of compound 94). The following compounds were prepared by thismethod:

-   4-(4-bromothiophen-2-yl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (95),-   (S)-4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (96),-   (R)-4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (97),-   8-(5-bromo-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (98),-   (S)-8-(5-bromo-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (99), and-   (R)-8-(5-bromo-2-fluorophenyl)-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (100).    The following table provides the compound number (column 1),    compound used in Step 1 (column 2), and compound used in Step 2    (column 3) to give the compound shown in column 4. An asterisk by    the compound number indicates the (S) isomer of    2-methylpropane-2-sulfinamide was used, while two asterisks    indicated the (R) isomer was used.

Comp. number Step 1 Step 2 Structure  95

  96**

  97*

 98

  99**

 100*

Example 8 Synthesis of4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine(102)

4-Methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine102 was prepared from4-(4-bromothiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine27 (prepared as described in Example 2) and5-(prop-1-ynyl)pyridin-3-ylboronic acid 101 in one Step as follows:

Step 1—synthesis of4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine(102)

4-(4-Bromothiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine(27, 35 mg, 0.1 mmol), 5-(prop-1-ynyl)pyridin-3-ylboronic acid (101, 33mg, 0.2 mmol), 1,1′-bis(diphenylphosphino)ferrocine palladium (II)dichloride (22 mg, 0.03 mmol) and Cs₂CO₃ (100 mg, 0.3 mmol) werecombined in 2.5 mL of DME and 0.8 mL of water. The mixture was flushedwith nitrogen for 2 minutes, then heated at 90° C. for 40 minutes. Themixture was diluted with 30 mL of EtOAc, washed with water and brine,and the organic phase was dried, filtered and the filtrate concentratedunder vacuum. The resulting material was purified by HPLC(acetonitrile/water with 0.1% TFA). Appropriate fractions were combinedand concentrated under vacuum to provide the desired compound as adi-TFA salt (102, 18 mg, 0.04 mmol). ¹H NMR (400 MHz, CD₃OD) δ: 8.77 (s,1H), 8.47 (s, 1H), 8.13 (s, 1H), 7.84 (d, 1H), 7.54 (d, 1H), 3.80-3.85(m, 2H), 3.52-3.63 (m, 2H), 2.96 (d, 1H), 2.40 (d, 1H), 2.10 (s, 3H),1.97-2.04 (m, 1H), 1.85-1.99 (m, 1H), 1.80 (s, 3H), 1.58-1.63 (m, 2H).MS: 382.1 m/z (M+H)⁺.

Additional compounds are prepared following the methods of this example,wherein4-(4-bromothiophen-2-yl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine27 is optionally replaced with a suitable bromo-(hetero)aryl compound(prepared by the methods of Examples 2, 4, 5 or 7) and5-(prop-1-ynyl)pyridin-3-ylboronic acid 101 is optionally replaced witha suitable boronic acid or boronic acid ester. The following compoundswere prepared by this method:

-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (103),-   (S)-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (104),-   (R)-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (105),-   4-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (106),-   4-(2-fluoro-5-(1-propyl-1H-pyrazol-4-yl)phenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (107),-   (S)-4-methyl-4-(5-methyl-4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (108),-   9,9-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine    (109),-   (S)-9,9-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine    (110),-   (S)-8-(2-fluoro-5-(5-(prop-1-ynyl)pyridin-3-yl)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (111),-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine    (112),-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (113), and-   5,5-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (114).    The following table provides the compound number (column 1),    Br-(hetero)aryl compound used (column 2), and boronic acid compound    used (column 3) to give the compound shown in column 4.    Identification data is provided in column 5.

Comp No. Br-(hetero)aryl Boronic acid Structure Identification 103

  Ex. 2-26

MS: 352.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.78 (d, 1H), 8.48 (d,1H), 8.17 (t, 1H), 7.85 (d, 1H), 7.52 (d, 1H), 2.94 (d, 1H), 2.44- 2.55(m, 2H), 2.32-2.43 (m, 1H), 2.11 (s, 3H), 1.87-1.97 (m, 1H), 1.83 (s,3H), 1.65- 1.75 (m, 1H). 104

  Ex. 2-28

MS: 382.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.77 (d, 1H), 8.48 (d,1H), 8.16 (t, 1H), 7.85 (d, 1H), 7.53 (d, 1H), 3.84 (m, 2H), 3.60 (m,2H), 2.98 (d, 1H), 2.41 (d, 1H), 2.10 (s, 3H), 2.08-1.98 (m, 1H),1.95-1.86 (m, 1H), 1.82 (s, 3H), 1.57 (m, 2H). 105

106

  Ex. 2-25

MS: 357.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 9.20 (s, 1H), 9.10 (s,2H), 7.82 (m, 1H), 7.73 (dd, 1H), 7.44 (dd, 1H), 3.84 (m, 2H), 3.57 (m,2H), 3.10 (d, 1H), 2.42 (d, 1H), 1.95-2.08 (m, 1H), 1.85-1.95 (m, 1H),1.84 (s, 3H), 1.50 (m, 2H). 107

  Ex. 2-25

MS: 387.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.05 (s, 1H), 7.86 (d,1H), 7.63 (m, 1H), 7.53 (dd, 1H), 7.23 (dd, 1H), 4.17 (t, 2H), 3.84 (m,2H), 3.57 (m, 2H), 3.08 (d, 1H), 2.35 (d, 1H), 1.83-2.08 (m, 4H), 1.81(s, 3H), 1.42-1.55 (m, 2H), 0.95 (t, 3H). 108

  Ex. 2-28

MS: 396.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.52 (m, 2H), 7.90 (d,1H), 7.05 (s, 1H), 3.89 (m, 2H), 3.65 (m, 2H), 2.90 (d, 1H), 2.50 (s,3H), 2.38 (d, 1H), 2.11 (s, 3H), 2.08-1.98 (m, 1H), 1.95-1.86 (m, 1H),1.79 (s, 3H), 1.67 (m, 2H). 109

  Ex. 2-31

MS: 416.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.77 (d, J = 2.0 Hz,1H), 8.47 (d, J = 1.6 Hz, 1H), 8.16 (s, 1H), 7.85 (d, J = 1.4 Hz, 1H),7.54 (d, J = 1.5 Hz, 1H), 2.93 (d, J = 15.0 Hz, 1H), 2.46 (d, J = 14.9Hz, 1H), 2.30-2.00 (m, 3H), 2.09 (s, 3H), 2.00- 1.80 (m, 2H), 1.79 (s,3H), 1.70-1.50 (m, 1H). 110

  Ex. 2-32

MS: 416.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.77 (d, J = 2.0 Hz,1H), 8.47 (d, J = 1.6 Hz, 1H), 8.16 (s, 1H), 7.85 (d, J = 1.4 Hz, 1H),7.54 (d, J = 1.5 Hz, 1H), 2.93 (d, J = 15.0 Hz, 1H), 2.46 (d, J = 14.9Hz, 1H), 2.30-2.00 (m, 3H), 2.09 (s, 3H), 2.00- 1.80 (m, 2H), 1.79 (s,3H), 1.70-1.50 (m, 1H). 111

  Ex. 2-33

MS: 364.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.70 (d, 1H), 8.58 (d,1H), 8.07 (m, 1H), 7.76 (m, 1H), 7.52 (d, 1H), 7.39 (dd, 1H), 3.11 (d,1H), 2.50-2.39 (m, 2H), 2.38 (d, 1H), 2.12 (s, 3H), 1.97-1.87 (m, 2H),1.83 (s, 3H), 1.65-1.75 (m, 1H), 1.63- 1.54 (m. 1H). 112

  Ex. 4-63

MS: 370.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CDCl₃) δ: 8.72 (s, 1H), 8.55 (s,1H), 7.91 (s, 1H), 7.49 (s, 1H), 7.18 (s, 1H), 3.73 (d, J = 10.4 Hz,1H), 3.41 (d, J = 14.4 Hz, 1H), 3.30 (d, J = 10.4 Hz, 1H), 3.17 (d, J =10.4 Hz, 1H), 2.55 (d, J = 10.4 Hz, 1H), 2.34-2.30 (m, 1H), 2.11 (s,3H), 1.90 (s, 3H). 113

  Ex. 5-72

MS: 398.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.77 (s, 1H), 8.47 (s,1H), 8.15 (s, 1H), 7.84 (d, J = 1.4 Hz, 1H), 7.52 (d, J = 1.4 Hz, 1H),3.87 (dt, J = 12.4, 4.0 Hz, 1H), 3.70-3.57 (m, 2H), 3.47 (dt, J = 10.1,2.5 Hz, 1H), 3.00 (d, J = 14.9 Hz, 1H), 2.40 (d, J = 14.9 Hz, 1H),2.10-2.00 (m, 1H), 2.09 (s, 3H), 1.95-1.83 (m, 1H), 1.86 (s, 3H), 1.62(ddd, J = 14.3, 10.4, 4.2 Hz, 1H), 1.44 (d, J = 13.7 Hz, 1H). 114

  Ex. 7-95

MS: 418.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.82 (d, 1H), 8.52 (d,1H), 8.20 (t, 1H), 8.03 (d, 1H), 7.67 (s, 1H), 4.01 (m, 1H), 3.79 (m,2H), 3.61 (m, 1H), 2.05-2.25 (m, 2H), 2.13 (s, 3H), 1.97 (d, 3H),1.84-1.97 (m, 1H), 1.57 (m, 1H).

Example 9 Synthesis ofN-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide(120)

N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide120 was prepared from4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine25 (prepared as described in Example 2) in five Steps as follows:

Step 1—synthesis of tert-butyl4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate(115)

tert-Butoxycarbonyl tert-butyl carbonate (0.3 g, 1.0 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.2 g, 2.0 mmol) and4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine(25, 0.3 g, 0.8 mmol) were combined in 10 mL of CH₂Cl₂. The mixture wasstirred at room temperature for 8 hours, then concentrated under vacuum.The resulting material was purified by flash column chromatography(hexane/EtOAc 0-50%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound as a whitesolid (115, 0.4 g, 0.7 mmol).

Step 2—synthesis of tert-butyl4-(5-azido-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate(116)

tert-butyl4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate(115, 70 mg, 0.15 mmol), sodium ascorbate (24 mg, 0.12 mmol), sodiumazide (30 mg, 0.46 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (13 mg,0.09 mmol), and copper sulfate pentahydrate (15 mg, 0.06 mmol) werecombined in 1.6 mL of EtOH and 0.4 mL of water. The resulting mixturewas flushed with nitrogen and heated at 80° C. for 1 hour. The reactionmixture was diluted with 30 mL of EtOAc, washed with saturated aqueousNaHCO₃ and brine and the organic portion was dried, filtered and thefiltrate concentrated under vacuum to provide the desired compound as ayellow solid (116, 61 mg, 0.14 mmol).

Step 3—synthesis of tert-butyl4-(5-amino-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate(117)

tert-butyl4-(5-azido-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate(116, 45 mg, 0.11 mmol) was dissolved in 5 mL of EtOH, and 9 mg of 10%Pd/C was added. The mixture was hydrogenated at 30 psi under H₂ for 1.5hours. The catalyst was removed by filtration, and the filtrateconcentrated under vacuum to provide the desired compound as a whitesolid (117, 40 mg, 0.10 mmol).

Step 4—synthesis of tert-butyl4-(2-fluoro-5-(5-fluoropicolinamido)phenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate(119)

tert-Butyl4-(5-amino-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate(117, 15 mg, 0.04 mmol), 5-fluoropicolinic acid (118, 6 mg, 0.045 mmol),and [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethyl-ammoniumhexafluorophosphate (19 mg, 0.05 mmol) were dissolved in 0.6 mL of DMF.The mixture was cooled over an ice-water bath andN-ethyl-N-isopropyl-propan-2-amine (7 mg, 0.057 mmol) was added. Themixture was stirred at room temperature for 30 minutes, then dilutedwith 10 mL of EtOAc, and washed with saturated aqueous NaHCO₃ and brine.The organic portion was dried, filtered and the filtrate concentratedunder vacuum to provide the desired compound as a yellow solid (119, 18mg, 0.035 mmol).

Step 5—synthesis ofN-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide(120)

tert-Butyl4-(2-fluoro-5-(5-fluoropicolinamido)phenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-ylcarbamate(119, 18 mg, 0.035 mmol) was dissolved in 0.2 mL of CH₂Cl₂ and 0.2 mL ofTFA was added. The resulting mixture was stirred at room temperature for30 minutes, then concentrated under vacuum. The resulting material waspurified by HPLC (acetonitrile/water with 0.1% TFA). Appropriatefractions were combined and concentrated under vacuum to provide thedesired compound as a di-TFA salt (120, 14 mg, 0.033 mmol). MS: 417.2m/z (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ: 8.64 (d, J=2.76, 1H), 8.32 (dd,J=4.52, 8.88, 1H), 8.07 (dd, J=2.68, 7.48, 1H), 7.8 (dt, J=2.76, 8.48,1H), 7.76 (m, 1H), 7.29 (dd, J=8.84, 11.96, 1H), 3.82-3.86 (m, 2H),3.55-3.58 (m, 2H), 3.09 (d, J=15.04, 1H), 2.36 (d, J=15.04, 1H),1.85-1.97 (m, 1H), 1.80 (s, 3H), 1.42-1.55 (m, 2H).

Additional compounds are prepared following the methods of this example,wherein4-(5-bromo-2-fluorophenyl)-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-2-amine25 is optionally replaced with a suitable bromo-(hetero)aryl compound(prepared by the methods of Examples 2-7) in Step 1 and5-fluoropicolinic acid 118 is optionally replaced with a suitablecarboxylic acid in Step 4. The following compounds were prepared by thismethod:

-   N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide    (121),-   (S)—N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide    (122),-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (123),-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide    (124),-   N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (125),-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (126),-   (R)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (127),-   (S)—N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (128),-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloropicolinamide    (129),-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-cyanopicolinamide    (130),-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloro-3-fluoropicolinamide    (131),-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-(trifluoromethyl)picolinamide    (132),-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloro-3-fluoropicolinamide    (133),-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)cyclopropanecarbox    amide (134),-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide    (135),-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-bromopicolinamide    (136),-   (S)—N-(3-(2-amino-9,9-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-cyclopropylpicolinamide    (137),-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-2-methyloxazole-4-carboxamide    (138),-   N-(3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-cyanopicolinamide    (139),-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-4-chloro-2-methoxybenzamide    (140),-   (S)—N-(3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-4-chlorobenzamide    (141),-   N-(3-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (142),-   (R)—N-(3-(6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (143),-   (S)—N-(3-(6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (144),-   (S)—N-(3-(6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloropicolinamide    (145),-   (S)—N-(3-(6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (146),-   N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (147),-   (S)—N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (148),-   (R)—N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (149),-   N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide    (150),-   (S)—N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide    (151),-   (R)—N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide    (152),-   (S)—N-(3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide    (153),-   (S)—N-(3-(5-amino-7-methyl-4-oxa-6-azaspiro[2.5]oct-5-en-7-yl)-4-fluorophenyl)-5-chloropicolinamide    (154),-   N-(3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (155),-   (S)—N-(3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (156),-   (R)—N-(3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (157),-   N-(3-(2-amino-5,5-difluoro-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide    (158),-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (159),-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-chloropicolinamide    (160),-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-cyanopicolinamide    (161),-   (R)—N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-cyanopicolinamide    (162),-   (S)—N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-cyanopicolinamide    (163),-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide    (164), and-   N-(3-(6-amino-9,9-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-2-methyloxazole-4-carboxamide    (165).    The following table provides the compound number (column 1),    Br-(hetero)aryl compound used in Step 1 (column 2), and carboxylic    acid compound used in Step 4 (column 3) to give the compound shown    in column 4. Identification data is provided in column 5.

Comp No. Step 1 bromo Step 4 acid Structure Identification 121

  Ex. 2-25

122

  Ex. 2-37

MS: 433.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.74 (d, 1H), 8.23(dd, 1H), 8.11 (dd, 1H), 8.06 (dd, 1H), 7.77 (m, 1H), 7.27 (dd, 1H),3.84 (m, 2H), 3.57 (m, 2H), 3.08 (d, 1H), 2.35 (d, 1H), 2.00 (m, 1H),1.88 (m, 1H), 1.81 (s, 3H), 1.42-1.57 (m, 2H). 123

  Ex. 2-36

MS: 451.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 10.63 (s, 1H), 8.60(d, J = 2.6 Hz, 1H), 8.28 (dd, J = 8.7, 4.5 Hz, 1H), 8.07-7.97 (m, 1H),7.81 (dt, J = 8.6, 2.8 Hz, 1H), 7.78-7.68 (m, 1H), 7.24 (dd, J = 11.9,8.9 Hz, 1H), 3.01 (d, J = 15.1 Hz, 1H), 2.38 (d, J = 15.1 Hz, 1H),2.30-1.65 (m, 7H), 1.78 (s, 3H), 1.50-1.36 (m, 1H). 124

  Ex. 2-36

MS: 467.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 10.67 (s, 1H), 8.71(d, J = 2.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.07 (dd, J = 8.4, 2.4Hz, 1H), 8.03 (dd, J = 7.5, 2.7 Hz, 1H), 7.80-7.70 (m, 1H), 7.24 (dd, J= 12.0, 8.8 Hz, 1H), 3.01 (d, J = 15.1 Hz, 1H), 2.38 (d, J = 15.1 Hz,1H), 2.30-1.65 (m, 7H), 1.78 (s, 3H), 1.50- 1.36 (m, 1H). 125

  Ex. 2-35

126

  Ex. 2-33

MS: 387.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.64 (d, 1H), 8.31(dd, 1H), 8.00 (m, 1H), 7.80 (dt, 1H), 7.77 (m, 1H), 7.27 (dd, 1H), 3.10(d, 1H), 2.44-2.52 (m, 1H), 2.32-2.43 (m, 2H), 1.86- 2.05 (m, 2H), 1.83(s, 3H), 1.61-1.74 (m, 1H), 1.49-1.58 (m, 1H). 127

  Ex. 2-34

128

  Ex. 2-37

MS: 417.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.64 (d, 1H), 8.31(dd, 1H), 8.07 (dd, 1H), 7.83 (m, 1H), 7.76 (m, 1H), 7.27 (dd, 1H), 3.84(m, 2H), 3.57 (m, 2H), 3.08 (d, 1H), 2.35 (d, 1H), 2.00 (m, 1H), 1.88(m, 1H), 1.81 (s, 3H), 1.42-1.57 (m, 2H). 129

  Ex. 2-33

MS: 403.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.73 (m, 1H), 8.22 (m,1H), 8.10 (dd, 1H), 8.00 (dd, 1H), 7.78 (m, 1H), 7.26 (dd, 1H), 3.10 (d,1H), 2.42-2.54 (m, 1H), 2.32-2.43 (m, 2H), 1.86- 2.05 (m, 2H), 1.83 (s,3H), 1.61-1.74 (m, 1H), 1.49-1.58 (m, 1H). 130

  Ex. 2-33

MS: 394.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 9.08 (m, 1H), 8.46(dd, 1H), 8.38 (dd, 1H), 8.04 (dd, 1H), 7.82 (m, 1H), 7.28 (dd, 1H),3.10 (d, 1H), 2.44-2.52 (m, 1H), 2.32-2.43 (m, 2H), 1.86- 2.05 (m, 2H),1.83 (s, 3H), 1.61-1.74 (m, 1H), 1.49-1.58 (m, 1H). 131

  Ex. 2-33

MS: 421.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.59 (d, 1H), 8.04(dd, 1H), 8.01 (dd, 1H), 7.69 (m, 1H), 7.26 (dd, 1H), 3.10 (d, 1H),2.44-2.52 (m, 1H), 2.32-2.43 (m, 2H), 1.86-2.05 (m, 2H), 1.83 (s, 3H),1.61-1.74 (m, 1H), 1.49-1.58 (m, 1H). 132

  Ex. 2-36

MS: 501.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 10.81 (s, 1H), 9.04(s, 1H), 8.43-8.35 (m, 2H), 8.10-8.03 (m, 1H), 7.81-7.74 (m, 1H), 7.26(dd, J = 11.9, 8.8 Hz, 1H), 3.02 (d, J = 15.2 Hz, 1H), 2.38 (d, J = 15.1Hz, 1H), 2.30-1.65 (m, 7H), 1.78 (s, 3H), 1.50- 1.36 (m, 1H). 133

  Ex. 2-36

MS: 485.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.57 (d, J = 1.4 Hz,1H), 8.10-8.04 (m, 1H), 8.02 (dd, J = 10.4, 1.9 Hz, 1H), 7.69-7.60 (m,1H), 7.24 (dd, J = 11.9, 8.8 Hz, 1H), 3.01 (d, J = 15.1 Hz, 1H), 2.38(d, J = 15.1 Hz, 1H), 2.30-1.65 (m, 7H), 1.77 (s, 3H), 1.50-1.36 (m,1H). 134

  Ex. 2-36

MS: 396.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 10.19 (s, 1H), 7.87(dd, J = 4.8,-2.6 Hz, 1H), 7.45-7.30 (m, 1H), 7.15 (dd, J = 11.9, 8.8Hz, 1H), 2.98 (d, J = 15.1 Hz, 1H), 2.34 (d, J = 15.1 Hz, 1H), 2.30-1.60(m, 9H), 1.73 (s, 3H), 1.00-0.90 (m, 2H), 0.90- 0.80 (m, 2H). 135

  Ex. 2-33

MS: 400.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.94 (d, 1H), 8.32 (d,1H), 8.31 (dd, 1H), 8.00 (m, 1H), 7.80 (dt, 1H), 7.77 (m, 1H), 7.26 (dd,1H), 4.11 (S, 3H), 3.12 (d, 1H), 2.43-2.55 (m, 1H), 2.32-2.43 (m, 2H),1.77- 2.08 (m, 2H), 1.83 (s, 3H), 1.61-1.75 (m, 1H), 1.49-1.58 (m, 1H).136

  Ex. 2-36

MS: 511.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.80 (d, J = 2.0 Hz,1H), 8.23 (dd, J = 8.4, 2.2 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.01 (dd,J = 7.4, 2.6 Hz, 1H), 7.76 (ddd, J = 8.8, 4.1, 2.7 Hz, 1H), 7.23 (dd, J= 11.9, 8.8 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H), 7.13- 7.04 (m, 3H), 3.02(d, J = 15.1 Hz, 1H), 2.38 (d, J = 15.1 Hz, 1H), 2.30-1.65 (m, 7H), 1.78(s, 3H), 1.48-1.37 (m, 1H). 137

  Ex. 2-36

MS: 473.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.51 (d, J = 2.0 Hz,1H), 8.07 (d, J = 8.2 Hz, 1H), 8.03 (dd, J = 7.4, 2.6 Hz, 1H), 7.73(ddd, J = 8.8, 4.1, 2.7 Hz, 1H), 7.60 (dd, J = 8.2, 2.2 Hz, 1H), 7.23(dd, J = 11.9, 8.9 Hz, 1H), 3.02 (d, J = 15.1 Hz, 1H), 2.37 (d, J = 15.1Hz, 1H), 2.30-1.65 (m, 8H), 1.78 (s, 3H), 1.48- 1.37 (m, 1H), 1.20-1.10(m, 2H), 0.90-0.82 (m, 2H). 138

  Ex. 2-33

MS: 373.3 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 10.00 (s, 1H), 8.40(s, 1H), 7.91 (m, 1H), 7.68 (m, 1H), 7.24 (dd, 1H), 3.09 (d, 1H), 2.55(s, 3H), 2.42-2.53 (m, 1H), 2.32-2.42 (m, 2H), 1.88- 2.04 (m, 2H), 1.82(s, 3H), 1.62-1.73 (m, 1H), 1.47-1.57 (m, 1H). 139

  Ex. 2-25

MS: 424.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 9.08 (m, 1H), 8.46(dd, 1H), 8.38 (dd, 1H), 8.10 (dd, 1H), 7.80 (m, 1H), 7.29 (dd, 1H),3.84 (m, 2H), 3.57 (m, 2H), 3.08 (d, 1H), 2.35 (d, 1H), 2.00 (m, 1H),1.88 (m, 1H), 1.81 (s, 3H), 1.42-1.57 (m, 2H). 140

  Ex. 2-33

MS: 432.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.01 (m, 1H), 7.84 (d,1H), 7.50 (m, 1H), 7.21-7.28 (m, 2H), 7.15 (dd, 1H), 4.04 (s, 3H), 3.11(d, 1H), 2.43-2.55 (m, 1H), 2.34-2.43 (m, 2H), 1.90-2.05 (m, 2H), 1.82(s, 3H), 1.63-1.75 (m, 1H), 1.50- 1.60 (m, 1H). 141

  Ex. 2-33

MS: 402.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 7.92-7.96 (m, 3H),7.50- 7.61 (m, 3H), 7.24 (dd, 1H), 3.10 (d, 1H), 2.44-2.52 (m, 1H),2.30-2.41 (m, 2H), 1.86- 2.05 (m, 2H), 1.82 (s, 3H), 1.63-1.75 (m, 1H),1.49-1.59 (m, 1H). 142

  Ex. 3-48

MS: 431.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CDCl₃) δ: 12.59 (s, 1H), 9.86(s, 1H), 8.48 (d, J = 2.7 Hz, 1H), 8.31 (dd, J = 8.7, 4.6 Hz, 1H), 8.06(m, 1H), 7.59 (m, 1H), 7.31 (dd, J = 7.2, 2.6 Hz, 1H), 7.09 (dd, J =11.7, 8.8 Hz, 1H), 3.14 (d, J = 15.1 Hz, 1H), 2.06 (d, J = 15.1 Hz, 1H),1.84 (s, 3H), 1.10-1.62 (m, 10H). 143

  Ex. 3-49

MS: 403.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.59 (d, J = 2.8 Hz,1H), 8.26 (dd, J = 8.8, 4.5 Hz, 1H), 7.89 (dt, J = 7.4, 2.9 Hz, 1H),7.80 (dt, J = 8.6, 2.8 Hz, 1H), 7.77-7.70 (m, 1H), 7.22 (dd, J = 11.9,8.8 Hz, 1H), 3.23 (d, J = 14.7 Hz, 1H), 2.52-2.41 (m, 1H), 2.39-2.30 (m,1H), 2.25 (d, J = 14.7 Hz, 1H), 2.02-1.66 (m, 4H), 1.84 (s, 3H). 144

  Ex. 3-50

MS: 403.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.60 (d, J = 2.8 Hz,1H), 8.26 (dd, J = 8.8, 4.4 Hz, 1H), 7.93 (dt, J = 7.5, 2.6 Hz, 1H),7.81 (dt, J = 8.6, 2.8 Hz, 1H), 7.76-7.70 (m, 1H), 7.22 (dd, J = 11.9,8.9 Hz, 1H), 3.23 (d, J = 14.7 Hz, 1H), 2.52-2.41 (m, 1H), 2.39-2.30 (m,1H), 2.25 (d, J = 14.7 Hz, 1H), 2.03-1.65 (m, 4H), 1.85 (s, 3H). 145

  Ex. 3-50

MS: 419.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.70 (d, J = 2.2 Hz,1H), 8.18 (d, J = 8.5 Hz, 1H), 8.07 (dd, J = 8.4, 2.4 Hz, 1H), 7.93 (dd,J = 7.4, 2.6 Hz, 1H), 7.74 (ddd, J = 9.0, 4.2, 2.7 Hz, 1H), 7.22 (dd, J= 11.9, 8.9 Hz, 1H), 3.23 (d, J = 14.8 Hz, 1H), 2.53-2.41 (m, 1H),2.40-2.30 (m, 1H), 2.25 (d, J = 14.7 Hz, 1H), 2.03-1.65 (m, 4H), 1.85(s, 3H). 146

  Ex. 4-64

MS: 405.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.63 (d, 1H), 8.31(dd, 1H), 8.00 (dd, 1H), 7.83 (m, 1H), 7.79 (m, 1H), 7.30 (dd, 1H), 3.71(d, 1H), 3.64 (d, 1H), 3.40 (d, 1H), 3.25 (d, 1H), , 2.50 (d, 1H), 2.44(d, 1H), 1.86 (s, 3H). 147

  Ex. 5-71

148

  Ex. 5-73

¹H NMR (400 MHz, CD₃OD) δ: 8.63 (d, 1H), 8.30 (d, 1H), 8.01 (m, 1H),7.84 (m, 1H), 7.77 (m, 1H), 7.27 (dd, 1H), 3.90 (dt, 1H), 3.65 (m, 2H),3.40-3.48 (m, 1H), 3.20 (d, 1H), 2.31 (d, 1H), 2.04-2.12 (m, 1H),1.88-1.94 (m, 1H), 1.87 (s, 3H), 1.47-1.57 (m, 1H), 1.30-1.37 (m, 1H).149

  Ex. 5-74

150

  Ex. 5-71

151

  Ex. 5-73

MS: 449.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.73 (d, 1H), 8.21 (d,1H), 8.10 (dd, 1H), 8.01 (dd, 1H), 7.76 (m, 1H), 7.26 (dd, 1H), 3.89(dt, 1H), 3.65 (m, 2H), 3.39-3.54 (m, 1H), 3.19 (d, 1H), 2.30 (d, 1H),2.04-2.12 (m, 1H), 1.88-1.94 (m, 1H), 1.86 (s, 3H), 1.47-1.57 (m, 1H),1.30-1.37 (m, 1H). 152

  Ex. 5-74

153

  Ex. 5-73

MS: 446.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.94 (d, 1H), 8.32 (d,1H), 8.01 (m, 1H), 7.72 (m, 1H), 7.26 (dd, 1H), 4.11 (s, 3H), 3.90 (dt,1H), 3.65 (m, 2H), 3.41-3.52 (m, 1H), 3.17 (d, 1H), 2.30 (d, 1H),2.04-2.12 (m, 1H), 1.88-1.94 (m, 1H), 1.87 (s, 3H), 1.47-1.57 (m, 1H),1.30-1.37 (m, 1H). 154

  Ex. 6-86

MS: 389.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.74 (d, 1H), 8.23 (d,1H), 8.05-8.15 (m, 2H), 7.81 (m, 1H), 7.26 (dd, 1H), 2.73 (d, 1H), 2.57(d, 1H), 1.90 (s, 3H), 1.16 (m, 1H), 0.95 (m, 2H), 0.27 (m, 1H). 155

  Ex. 7-94

MS: 453.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.64 (d, 1H), 8.32 (m,1H), 8.18 (m, 1H), 7.83-7.89 (m, 2H), 7.30 (dd, 1H), 4.01 (m, 1H), 3.90(m, 1H), 3.71-3.79 (m, 2H), 2.23 (m, 2H), 1.98 (bs, 3H), 1.84-1.98 (m,2H) 156

157

  Ex. 7-97

MS: 453.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.63 (d, 1H), 8.31(dd, 1H), 8.04 (dd, 1H), 7.84 (m, 2H), 7.18 (dd, 1H), 3.94 (m, 1H),3.68-3.85 (m, 3H), 2.09 (m, 2H), 1.83 (bs, 3H), 1.79 (m, 2H) 158

  Ex. 7-94

MS: 469.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.75 (d, 1H), 8.24 (d,1H), 8.18 (m, 1H), 8.11 (dd, 1H), 7.88 (m, 2H), 7.30 (dd, 1H), 4.01 (m,1H), 3.90 (m, 1H), 3.68-3.80 (m, 2H), 2.23 (m, 2H), 2.06 (bs, 3H),1.84-2.00 (m, 2H) 159

  Ex. 7-98

MS: 423.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.64 (d, 1H), 8.32(dd, 1H), 8.20 (dd, 1H), 7.82-7.89 (m, 2H), 7.30 (dd, 1H), 2.90 (m, 1H),2.50 (m, 1H), 2.30 (m, 1H), 2.11 (m, 2H), 2.03 (s, 3H), 1.83 (m, 1H) 160

  Ex. 7-98

MS: 439.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.74 (d, 1H), 8.22 (d,1H), 8.19 (dd, 1H), 8.10 (dd, 1H), 7.87 (m, 1H), 7.29 (dd, 1H), 2.90 (m,1H), 2.49 (m, 1H), 2.29 (m, 1H), 2.11 (m, 2H), 2.02 (s, 3H), 1.82 (m,1H) 161

  Ex. 7-98

162

  Ex. 7-100

MS: 430.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 9.08 (d, 1H), 8.46(dd, 1H), 8.39 (dd, 1H), 8.14 (dd, 1H), 7.89 (m, 1H), 7.26 (dd, 1H),2.86 (m, 1H), 2.42 (m, 1H), 2.22 (m, 1H), 2.07 (m, 2H), 1.93 (s, 3H),1.78 (m, 1H) 163

  Ex. 7-99

164

  Ex. 7-98

MS: 436.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.95 (d, 1H), 8.33 (d,1H), 8.20 (dd, 1H), 7.84 (m, 1H), 7.30 (dd, 1H), 4.11 (s, 3H), 2.91 (m,1H), 2.50 (m, 1H), 2.29 (m, 1H), 2.11 (m, 2H), 2.03 (s, 3H), 1.83 (m,1H) 165

  Ex. 7-98

MS: 409.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 8.40 (s, 1H), 8.09(dd, 1H), 7.76 (m, 1H), 7.30 (dd, 1H), 2.90 (m, 1H), 2.55 (s, 3H), 2.48(m, 1H), 2.28 (m, 1H), 2.08 (m, 2H), 2.00 (s, 3H), 1.82 (m, 1H)

Example 10 Synthesis of(S)-8-(2-fluoro-5-((5-fluoropyridin-2-yl)methylamino)phenyl)-8-methyl-5-oxa-7-azaspirop[3.5]non-6-en-6-amine(169)

(S)-8-(2-fluoro-5-((5-fluoropyridin-2-yl)methylamino)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine169 was prepared in from (S)-tert-butyl8-(5-amino-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate166 (prepared by the methods of Example 9, for example isolating afterStep 3 in the preparation of compound 126) and 5-fluoropicolinaldehyde167 in two Steps as follows:

Step 1—synthesis of (S)-tert-butyl8-(2-fluoro-5-((5-fluoropyridin-2-yl)methylamino)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate(168)

Sodium triacetoxyborohydride (0.02624 g, 0.1238 mmol) was added to asolution of (S)-tert-butyl8-(5-amino-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate(166, 0.03 g, 0.08255 mmol) and 5-fluoropicolinaldehyde (167, 0.01239 g,0.09906 mmol) in 1 mL of CH₃OH and the resulting solution was stirred atroom temperature for 18 hours. The reaction mixture was concentratedunder vacuum and the resulting material purified by silica gelchromatography (ISCO, hexane/EtOAc 0-100%). Appropriate fractions werecombined and concentrated under vacuum to provide the desired compound(168, 0.022 g, 0.04656 mmol, 56.40%) MS: 473.3 m/z (M+H)⁺.

Step 2—synthesis of(S)-8-(2-fluoro-5-((5-fluoropyridin-2-yl)methylamino)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine(169)

Trifluoroacetic acid (0.5 mL) was added to a solution of (S)-tert-butyl8-(2-fluoro-5-((5-fluoropyridin-2-yl)methylamino)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate(168, 0.025 g, 0.05291 mmol) in 0.5 mL of CH₂Cl₂. The resulting solutionwas stirred at room temperature for 30 minutes, then concentrated undervacuum and the residue was purified by preparative HPLC. Appropriatefractions were combined and concentrated under vacuum to provide thedesired compound (169, 0.009 g, 0.02417 mmol). MS: 373.2 m/z (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ: 11.95 (s, 1H), 8.45 (s, 1H), 7.46 (m, 2H), 6.86(dd, J=11.1, 8.7 Hz, 1H), 6.52 (m, 2H), 4.42 (s, 2H), 3.10 (d, J=14.6Hz, 1H), 2.39 (m, 1H), 2.20 (m, 1H), 2.07 (d, J=14.6 Hz, 1H), 1.83 (m,2H), 1.74 (s, 3H), 1.48-1.66 (m, 2H).

Example 11 Synthesis of(S)-8-(5-(7-chloroquinazolin-4-ylamino)-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine(173)

(S)-8-(5-(7-chloroquinazolin-4-ylamino)-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine173 was prepared from 7-chloroquinazolin-4(3H)-one 170 in three Steps asfollows:

Step 1—synthesis of 4,7-dichloroquinazoline (171)

7-Chloro-3H-quinazolin-4-one (170, 0.155 g, 0.85830 mmol) was dissolvedin 1 mL of POCl₃ in a screw cap vial. The vial was sealed and placed ina 100° C. oil bath for 3 hours. The resulting solution was concentratedunder vacuum and co-concentrated from toluene three times to provide thedesired compound (171, 0.162 g, 0.81391 mmol, 94.828%). MS: 199.0 m/z(M+H)⁺.

Step 2—synthesis of (S)-tert-butyl8-(5-(7-chloroquinazolin-4-ylamino)-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate(172)

(S)-tert-butyl8-(5-amino-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate(166, 0.026 g, 0.07155 mmol), 4,7-dichloroquinazoline (171, 0.02136 g,0.1073 mmol) and potassium carbonate (0.01978 g, 0.1431 mmol) weredissolved in 0.5 mL of isopropanol in a screw cap vial. The vial wassealed and placed in a 70° C. oil bath for 3 hours, then concentratedunder vacuum and the residue was purified by silica gel chromatography(ISCO, CH₂Cl₂/MeOH 0-10%). Appropriate fractions were combined andconcentrated under vacuum to provide the desired compound (172, 0.032 g,0.06084 mmol, 85.03%). MS: 526.2 m/z (M+H)⁺.

Step 3—synthesis of(S)-8-(5-(7-chloroquinazolin-4-ylamino)-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine(173)

Trifluoroacetic acid (1 mL) was added to a solution of (S)-tert-butyl8-(5-(7-chloroquinazolin-4-ylamino)-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate(172, 0.03 g, 0.05703 mmol) in 1 mL of CH₂Cl₂. The reaction was stirredat room temperature for 1 hour, then concentrated under vacuum, and theresidue was purified by preparative HPLC. Appropriate fractions werecombined and concentrated under vacuum to provide the desired compound(173, 0.018 g, 0.04226 mmol, 74.10%). MS: 426.1 m/z (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ: 11.20 (s, 1H), 8.75 (s, 1H), 8.61 (d, J=8.8 Hz, 1H), 8.15(m, 1H), 7.92 (m, 2H), 7.55 (d, J=7.1 Hz, 1H), 7.18 (dd, J=11.5, 8.9 Hz,1H), 3.11 (d, J=14.8 Hz, 1H), 2.46 (m, 1H), 2.28 (d, J=14.8 Hz, 1H),1.99-2.25 (m, 5H), 1.69 (s, 3H), 1.52-1.60 (m, 2H).

Example 12 Synthesis of(S,E)-8-(2-fluoro-5-(4-fluorostyryl)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine(177)

(S,E)-8-(2-fluoro-5-(4-fluorostyryl)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine177 was prepared from (S)-tert-butyl8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate174 (prepared by the methods of Step 1 of Example 9, starting fromcompound 33 of Example 2), and (E)-4-fluorostyrylboronic acid 175 in twoSteps as follows:

Step 1—synthesis of (S,E)-tert-butyl8-(2-fluoro-5-(4-fluorostyryl)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate(176)

(S)-tert-butyl8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate(174, 51 mg. 0.12 mmol), (E)-4-fluorostyrylboronic acid (175, 40 mg,0.24 mmol), 1,1′-bis(diphenylphosphino)ferrocine palladium (II)dichloride (26 mg, 0.036 mmol) and cesium carbonate (117 mg, 0.36 mmol)were combined in 3.25 mL of DME and 1 mL of water. The mixture wasflushed with nitrogen for 2 minutes and then heated at 85° C. for 30minutes. The mixture was cooled to room temperature, then diluted with50 mL of EtOAc, washed with 10 mL, then 5 mL of water and 5 mL of brine.The organic extract was dried with Na₂SO₄, filtered and the filtrateconcentrated under vacuum to provide the desired compound (176, 110 mg).

Step 2—synthesis of (S,E)-tert-butyl8-(2-fluoro-5-(4-fluorostyryl)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate(177)

(S,E)-tert-butyl8-(2-fluoro-5-(4-fluorostyryl)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate(176, 110 mg) was taken up into 2 mL of CH₂Cl₂ and 1 mL of TFA was addeddropwise at room temperature. The mixture was stirred for 60 minutes atroom temperature, then concentrated under vacuum. The resulting materialwas purified by preparative reverse-phase HPLC. Appropriate fractionswere combined and concentrated under vacuum to provide the desiredcompound as a mono-TFA salt (177, 47 mg, ˜81% yield). MS: 369.2 m/z(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ: 7.64-7.58 (m, 2H), 7.57-7.4 (m, 1H),7.39 (dd, 1H), 7.13-7.04 (m, 3H), 7.00 (d, 2H), 3.11 (d, 1H), 2.50 (m,1H), 2.28 (m, 1H) 2.21 (d, 1H), 1.97-1.84 (m, 2H), 1.85 (s, 3H),1.68-1.59 (m, 1H), 1.58-1.43 (m, 1H).

Additional compounds are prepared following the methods of this example,optionally replacing (S)-tert-butyl8-(5-bromo-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-ylcarbamate174 with a suitable Boc protected bromo-(hetero)aryl compound (similarlyprepared by the methods of Examples 9 Step 1) and optionally replacing(E)-4-fluorostyrylboronic acid 175 with a suitable boronic acid inStep 1. The following compounds were prepared by this method:

-   (S,E)-8-(2-fluoro-5-(4-fluorostyryl)phenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (178), and-   (S,E)-8-(5-(4-chlorostyryl)-2-fluorophenyl)-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (179).    The following table provides the compound number (column 1),    Br-(hetero)aryl compound used in Step 1 (column 2), and boronic acid    compound used in Step 1 (column 3) to give the compound shown in    column 4. Identification data is provided in column 5.

Comp No. Step 1 bromo Step 1 boronic acid Structure Identification 178

MS: 433.2 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 7.69-7.62 (m, 1H),7.62- 7.54 (m, 2H), 7.49 (dd, J = 8.0, 2.1 Hz, 1H), 7.21 (dd, J = 11.3,8.5 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H), 7.13-7.04 (m, 3H), 3.03 (d, J =15.1 Hz, 1H), 2.38 (d, J = 15.1 Hz, 1H), 2.30-1.60 (m, 7H), 1.77 (s,3H), 1.52- 1.38 (m, 1H). 179

MS: 385.1 m/z (M + H)⁺ ¹H NMR (400 MHz, CD₃OD) δ: 7.69-7.62 (m, 1H),7.64- 7.55 (m, 2H), 7.50-7.35 (m, 3H), 7.30-7.10 (m, 3H), 3.10 (d, 1H),2.51 (m, 1H), 2.30 (m, 1H) 2.35 (d, 1H), 1.97-1.84 (m, 2H), 1.80 (s,3H), 1.70- 1.60 (m, 1H), 1.58-1.48 (m, 1H).

Example 13 Synthesis of(S)-4-(2-fluoro-5-(3-methoxypyridin-2-ylamino)phenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine(182)

(S)-4-(2-fluoro-5-(3-methoxypyridin-2-ylamino)phenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine182 was prepared from (S)-tert-butyl4-(5-amino-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-ylcarbamate180 (prepared by the methods of Example 9, for example isolating afterStep 3 in the preparation of compound 148), and2-fluoro-3-methoxypyridine 181 in one Step as follows:

Step 1—synthesis of(S)-4-(2-fluoro-5-(3-methoxypyridin-2-ylamino)phenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine(182)

(S)-tert-butyl4-(5-amino-2-fluorophenyl)-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-ylcarbamate(180, 20 mg, 0.048 mmol) was dissolved in 1 mL of isopropanol, and2-fluoro-3-methoxypyridine (181, 12 mg, 0.098 mmol) was added. Themixture was stirred at room temperature for 5 minutes, then 0.1 mL ofHCl (4N in dioxane) was added. The resulting mixture was heated at 100°C. for 2 days, then concentrated under vacuum. The resulting materialwas purified by HPLC (acetonitrile/water with 0.1% TFA). Appropriatefractions were combined and concentrated under vacuum to provide thedesired compound as a di-TFA salt (182, 8.3 mg, 0.02 mmol). MS: 417.2m/z (M+H)⁺. NMR (400 MHz, CD₃OD) δ: 7.46-7.59 (m, 4H), 7.34 (dd, 1H),6.97 (t, 1H), 4.07 (s, 3H), 3.89 (dt, 1H), 3.57-3.68 (m, 2H), 3.41-3.52(m, 1H), 3.16 (d, 1H), 2.32 (d, 1H), 2.04-2.12 (m, 1H), 1.88-1.94 (m,1H), 1.87 (s, 3H), 1.47-1.57 (m, 1H), 1.30-1.37 (m, 1H).

Example 14 Synthesis of Additional Compounds

The methods as described in Schemes 1-11, Examples 1-13, or variationsas would be known to one of skill in the art are used to make additionalcompounds. The following compounds are prepared:

-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-3-azaspiro[5.5]undec-2-en-2-amine    (500),-   N-(3-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-chloropicolinamide    (502),-   N-(3-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-cyanopicolinamide    (503),-   7-methyl-7-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-4-thia-6-azaspiro[2.5]oct-5-en-5-amine    (504),-   7-methyl-7-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-4-oxa-6-azaspiro[2.5]oct-5-en-5-amine    (505),-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-thia-7-azaspiro[3.5]non-6-en-6-amine    (506),-   4′-methyl-4′-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-4′,5′-dihydrospiro[bicyclo[3.1.0]hexane-3,6′-[1,3]thiazin]-2′-amine    (508),-   7-methyl-7-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-4-thia-6-azaspiro[2.5]oct-5-en-5-amine    (509),-   5-(5-(5-amino-7-methyl-4-thia-6-azaspiro[2.5]oct-5-en-7-yl)-4-chlorothiophen-2-yl)nicotinonitrile    (510),-   N-(3-(5-amino-7-methyl-4-thia-6-azaspiro[2.5]oct-5-en-7-yl)-4-fluorophenyl)-5-fluoropicolinamide    (511),-   N-(3-(5-amino-7-methyl-4-thia-6-azaspiro[2.5]oct-5-en-7-yl)-4-fluorophenyl)-5-fluoropicolinamide    (512),-   N-(3-(6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (513),-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,8-dioxa-3-azaspiro[5.5]undec-2-en-2-amine    (515),-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-2,5-dioxa-7-azaspiro[3.5]non-6-en-6-amine    (516),-   5-(5-(6-amino-8-methyl-2,5-dioxa-7-azaspiro[3.5]non-6-en-8-yl)thiophen-3-yl)nicotinonitrile    (517),-   8-(4-(5-(cyclopropylethynyl)pyridin-3-yl)thiophen-2-yl)-8-methyl-2,5-dioxa-7-azaspiro[3.5]non-6-en-6-amine    (518),-   8-methyl-8-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-2,5-dioxa-7-azaspiro[3.5]non-6-en-6-amine    (519),-   5-(5-(6-amino-8-methyl-2,5-dioxa-7-azaspiro[3.5]non-6-en-8-yl)-4-chlorothiophen-2-yl)nicotinonitrile    (520),-   N-(3-(6-amino-8-methyl-2,5-dioxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (521),-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-8-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (523),-   5-(5-(6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl)thiophen-3-yl)nicotinonitrile    (524),-   8-(4-(5-(cyclopropylethynyl)pyridin-3-yl)thiophen-2-yl)-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine    (525),-   8-methyl-8-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-6-amine    (526),-   5-(5-(6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-chlorothiophen-2-yl)nicotinonitrile    (527),-   N-(3-(6-amino-8-methyl-2-oxa-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (528),-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-2,5-dithia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide    (529),-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-8-thia-3-azaspiro[5.5]undec-2-en-2-amine-8,8-dioxide    (530),-   8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide    (531),-   5-(5-(6-amino-8-methyl-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)thiophen-3-yl)nicotinonitrile    (532),-   8-(4-(5-(cyclopropylethynyl)pyridin-3-yl)thiophen-2-yl)-8-methyl-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide    (533),-   8-methyl-8-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide    (534),-   5-(5-(6-amino-8-methyl-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)-4-chlorothiophen-2-yl)nicotinonitrile    (535),-   N-(3-(6-amino-8-methyl-5-oxa-2-thia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)-4-fluorophenyl)-5-fluoropicolinamide    (536),-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,9-dithia-3-azaspiro[5.5]undec-2-en-2-amine-9,9-dioxide    (537),-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-oxa-9-thia-3-azaspiro[5.5]undec-2-en-2-amine-9,9-dioxide    (538),-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1,8-dithia-3-azaspiro[5.5]undec-2-en-2-amine-8,8-dioxide    (539),-   5-(5-(6-amino-8-methyl-2,5-dithia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)thiophen-3-yl)    nicotinonitrile (540),-   8-(4-(5-(cyclopropylethynyl)pyridin-3-yl)thiophen-2-yl)-8-methyl-2,5-dithia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide    (541),-   8-methyl-8-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-2,5-dithia-7-azaspiro[3.5]non-6-en-6-amine-2,2-dioxide    (542),-   5-(5-(6-amino-8-methyl-2,5-dithia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)-4-chlorothiophen-2-yl)nicotinonitrile    (543),-   N-(3-(6-amino-8-methyl-2,5-dithia-7-azaspiro[3.5]non-6-en-8-yl-2,2-dioxide)-4-fluorophenyl)-5-fluoropicolinamide    (544),-   1-(6-amino-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-thia-7-azaspiro[3.5]non-6-en-2-yl)ethanone    (545),-   1-(6-amino-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-oxa-7-azaspiro[3.5]non-6-en-2-yl)ethanone    (546),-   N-(3-(2-acetyl-6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (547),-   N-(3-(2-acetyl-6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (548),-   N-(3-(6-amino-2,2-difluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (549),-   N-(3-(6-amino-2,2-difluoro-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (551),-   N-(3-(2-amino-9,9-difluoro-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (552),-   2,2-difluoro-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-thia-7-azaspiro[3.5]non-6-en-6-amine    (553),-   9,9-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (554),-   2,2,9,9-tetrafluoro-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-thia-7-azaspiro[3.5]non-6-en-6-amine    (555),-   5,5,9,9-tetrafluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (556),-   9,9-difluoro-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-thia-7-azaspiro[3.5]non-6-en-6-amine    (557),-   10,10-difluoro-9-methyl-9-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-6-thia-8-azaspiro[4.5]dec-7-en-7-amine    (558),-   5,5-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (559),-   5,5-difluoro-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (560),-   N-(3-(6-amino-2,2,9,9-tetrafluoro-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluorophenyl)-5-fluoropicolinamide    (561),-   N-(3-(2-amino-5,5,9,9-tetrafluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (562),-   N-(3-(7-amino-10,10-difluoro-9-methyl-6-oxa-8-azaspiro[4.5]dec-7-en-9-yl)-4-fluorophenyl)-5-fluoropicolinamide    (564),-   N-(3-(2-amino-5,5-difluoro-4-methyl-1-oxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluorophenyl)-5-fluoropicolinamide    (565),-   3-(2-amino-4-methyl-9-oxa-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzamide    (569),-   3-(2-amino-4-methyl-1,9-dioxa-3-azaspiro[5.5]undec-2-en-4-yl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzamide    (570),-   3-(6-amino-8-methyl-5-oxa-7-azaspiro[3.5]non-6-en-8-yl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzamide    (571), and-   3-(6-amino-8-methyl-5-thia-7-azaspiro[3.5]non-6-en-8-yl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzamide    (572)-   4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (573),-   9-methyl-9-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-6-thia-8-azaspiro[4.5]dec-7-en-7-amine    (574),-   (S)-4-methyl-4-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (575),-   (S)-9-methyl-9-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-6-thia-8-azaspiro[4.5]dec-7-en-7-amine    (576),-   9-methyl-9-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-1-(pyrrolidin-1-yl)-6-thia-8-azaspiro[4.5]dec-7-en-7-amine    (577),-   4-(1-(5-bromopyridin-3-yl)-1H-pyrazol-4-yl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (578),-   (R)-5-(5-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)thiophen-3-yl)nicotinonitrile    (579),-   4-methyl-4-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (580),-   (S)-4-methyl-4-(1-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-4-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (581),-   4-methyl-4-(1-methyl-3-(5-(prop-1-ynyl)pyridin-3-yl)-1H-pyrazol-5-yl)-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (582),-   (S)-4-(3-chloro-5-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (583),-   4-(3-chloro-5-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-2-amine    (584),-   (S)-5-(5-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-chlorothiophen-2-yl)nicotinonitrile    (585),-   5-(5-(2-amino-4-methyl-1-thia-3-azaspiro[5.5]undec-2-en-4-yl)-4-chlorothiophen-2-yl)nicotinonitrile    (586), and-   2,2-difluoro-8-methyl-8-(4-(5-(prop-1-ynyl)pyridin-3-yl)thiophen-2-yl)-5-oxa-7-azaspiro[3.5]non-6-en-6-amine    (587).    These compounds having the following structures:

Example A In Vitro Protease Activities

BACE1 activity can be assessed in an AlphaScreen® assay. Compounds to beassessed (e.g. compounds as described in the above examples) areserially diluted 1:4 in DMSO, then plated by diluting 10 μL of compoundwith 40 μl of assay buffer (lx PBS, 0.01% Tween-20, pH 7.0, 0.05% BSA).The diluted compound is transferred (4 μl per well) to a 386 well assayplate and 4 μL of BACE1 enzyme (20 mg/mL) is added and incubated for 15minutes. This assay uses a probe that is a BACE1 binding sight ligandlinked to biotin, which can be displaced by test compound dependent oncompound binding affinity. This of biotinylated probe (4 μL) is addedand incubated for 1 hour, followed with 4 μL of donor and acceptor beadmixture and incubated for 2 hours. The fluorescent signal is read on aplate reader and the value as a function of compound concentration isused to determine the IC₅₀. Compounds are also assessed for BACE1 andCathepsin D activity using an FP Assay. Compounds to be assessed (e.g.compounds as described in the above examples) are serially diluted 1:3with DMSO and each concentration point is transferred to a 96 wellplate, 6 μL per well, followed by addition of 194 μL of assay buffer(100 mM sodium acetate, pH 4.5 with 0.001% Tween-20). A 10 μL compoundsample from this plate is transferred to a well of a 384 well plate andcombined with 10 μL per well of BACE1 enzyme (0.3 nM in assay buffer) orCathepsin D enzyme (1.8 nM in assay buffer) and the plate is incubatedat room temperature for 30 minutes. Substrate (0.45 μM for BACE1 or 0.45nM for Cathepsin D in assay buffer) is added, 10 μL per well, and theplate is incubated at 37° C., 3 hours for BACE1 or 2 hours for CathepsinD. The reaction is stopped by adding 30 μL per well of cold 1.5 μMStreptavidin Immunopure and incubated for 15 minutes at room temperatureand the fluorescent signal determined, excitation 485-20 and Emission530-25, and the value as a function of compound concentration is used todetermine the IC₅₀.

BACE1 inhibition is also assessed in a cellular assay. HEKp293 cellstransfected with APP751 gene (SWE293, American Type Culture CollectionCRL-1563) are used to assess compounds for reduction in levels of Aβpeptide production. SWE293 cell medium is DMEM supplemented with 10%fetal bovine serum and 2 mM L-glutamine, 1.0 mM sodium pyruvate, 25 mMHepes Buffer, 0.4 mg/mL geneticin (G418, Gibco BRL 860-181IIJ). Cellsare maintained diluting 1:10 for 4 days in T-150 flask and 35 mL of cellmedia. For plating, cells are rinsed with 5 mL of 1×PBS, trypsinizedwith 4 mL of 0.05% Tripsin for 1 minute, and 12 mL of cell media isadded. These are centrifuged at 1000 rpm for 4 minutes and the mediaaspirated, then 8 mL of media per flask is added. Based on cell count,appropriate amounts of cell and cell media are combined, and 180 μl perwell are plated (96 well) and the plates are incubated overnight at 37°C., 5% CO₂. Compounds to be tested are serially diluted 1:3 in DMSO andtwice in media (without G418) in V-bottom plates and incubated at roomtemperature. Plated cells are washed with media, 3×50 μL per well and 17μL per well of appropriate dilution of compound is added. Plates areincubated for 2 hours, and the wash steps, compound addition andincubation are repeated. Sample is transferred to capture plate(prepared with 266 antibody, see e.g. Johnson-Wood et al., PNAS February1997, 94: 1550-1555), along with a standard curve of Aβ1-40. ELISA assayis used to assess Aβ levels, washing with TBS, 0.05% Tween20 pH 7.5,then adding 1.3 mg/mL 3D6 antibody 1:900 in specimen diluents withthimericol is added (100 μL per well) and incubated for 1 hour. Washstep is repeated and Streptavidin-AP diluted 1:1000 in specimen diluentswith thimerisol is added (100 μL per well) and incubated for 1 hour.Wash step is repeated and fluorescent substrate is added, 100 μL perwell and incubated for 10 minutes followed by reading the fluorescentsignal on a plate reader. Fluorescent signal is compared to standardcurve to assess Aβ peptide levels, which are plotted as a function ofconcentration to assess the effective concentration of the compound(dose at which Aβ level is reduced by 50%, ED₅₀).

Compounds as described herein (compounds of Formula I, e.g., compoundsof the above Examples) are tested for their in vitro BACE1 or BACE2activity in biochemical and cell assays. The following table summarizesexemplary compounds from the Examples above and their in vitro IC₅₀values for BACE1 inhibition and compared to Cathepsin D, and their invitro effective concentration (ED₅₀ values) for BACE1 inhibition inHEKp293 SWEAB cells as determined using the methods as described herein.Compounds are identified by the Example number and compound numberidentification given in the Example. For IC₅₀ values in the table, ASindicates values from the AlphaScreen® assay described above, while FPindicates values for the FP BACE1 or Cathepsin D assays as describedabove. SWE293 indicates the ED₅₀ value for the cellular assay. Thefollowing table summarizes exemplary compounds from the Examples above.

Example/ BACE1 AS BACE1 FP CatD FP SWE293 Compound No. IC₅₀ (μM) IC₅₀(μM) IC₅₀ (μM) ED₅₀ (μM) 8-102 0.069 2.29 4.43 0.365 8-103 0.030 1.367.92 0.582 8-104 0.016 0.406 14.8 0.157 8-105 1.33 84.9 5.25 7.47 8-1060.569 12.6 >30 0.673 8-107 1.677 34.1 20.8 1.725 8-108 0.0175 1.12 9.320.485 8-109 0.068 1.16 6.29 0.621 8-110 0.026 0.96 5.57 0.305 8-1110.088 3.51 5.08 0.391 8-112 0.017 0.227 0.222 8-113 <0.007 0.160 1.880.184 8-114 0.2205 0.626 5.54 2.12 9-120 0.019 0.282 >30 0.013 9-1210.009 0.073 >30 0.006 9-122 0.012 0.059 >30 0.004 9-123 0.0087 0.270 >300.019 9-124 0.0045 0.060 >30 0.011 9-125 0.029 0.366 >30 0.067 9-1260.011 0.321 >30 0.080 9-127 1.306 7.44 >30 >10 9-128 0.004 0.112 >300.009 9-129 0.0083 0.107 >30 0.037 9-130 0.006 0.046 >30 0.0054 9-1310.0057 0.087 >30 0.046 9-132 0.006 0.011 9-133 0.009 0.016 >30 0.0169-134 0.801 2.33 0.882 9-135 0.0105 0.281 >30 0.027 9-136 0.0070.050 >30 0.0089 9-137 0.017 1.83 0.088 9-138 0.011 0.299 >30 0.0239-139 0.009 0.048 >30 0.005 9-140 0.101 9.11 0.342 9-141 0.01750.839 >30 0.109 9-142 0.006 0.028 0.012 9-143 >7.5 51.8 >30 6.22 9-1440.008 0.027 >30 0.009 9-145 0.0045 0.0019 >30 0.002 9-146 0.00980.119 >30 0.022 9-147 0.008 0.029 15.6 <0.004 9-148 0.0068 0.029 >300.0014 9-149 >1 8.49 21.5 9-150 0.009 0.004 10.6 <0.004 9-151 0.00970.005 >30 0.0004 9-152 1.56 10.8 9-153 0.033 >30 <0.123 9-154 0.00750.113 >30 0.020 9-155 0.031 0.277 >30 0.177 9-156 >30 >30 >30 9-1570.045 0.300 >30 0.166 9-158 0.015 0.094 19.6 0.182 9-159 0.040 0.210 >300.225 9-160 0.0195 0.066 >30 0.268 9-161 0.0135 0.066 >30 0.038 9-1620.015 0.040 >30 0.039 9-163 13.4 38.1 >30 9-164 0.0275 0.464 >30 0.1959-165 0.034 0.496 >30 0.176 10-169  3.72 179 5.61 11-173  8.55 0.68712-177  1.16 21.7 1.21 12-178  1.96 13.1 2.13 12-179  0.51 4.64 1.3413-182  0.002 0.032 14.7 <0.123

Example B In Vivo Activities

Ability of a compound as described herein to reduce the level of Aβpeptide in vivo was determined in a Sprague Dawley rat model. Compoundswere dosed orally in female Sprague Dawley rats, along with a vehiclecontrol, five rats per dose group. Compounds were formulated in 5%DMSO/0.5% methylcellulose, and dosed at various amounts (10 mL/kg), and10 mL/kg vehicle by oral gavage. CSF was collected from the cisternmagna under isoflurane anesthesia, frozen on dry ice and stored at −80°C. until assessed for Aβ peptide levels. Rats were terminated 3 hourspost dosing, and cortical brain samples were collected, frozen on dryice and stored at −80° C. until assessed for Aβ peptide levels. Corticalbrain samples were homogenized in 5 M guanidine and Aβ peptide wasquantitated in these brain samples as well as plasma samples in an ELISAassay, where Aβ x-40 ELISA detects Aβ peptide N-terminal sequencescontaining the transmembrane region and ending at amino acid 40 at theC-terminus. The ELISA was performed as described in Johnson-Wood et al.,PNAS February 1997, 94: 1550-1555, using capture antibody 266 (Aβ 16-23specific) and biotinylated 2G3 (Aβ 40 specific) as reporter antibody.Results of cortical and plasma Aβ x-40 levels were statisticallyanalyzed separately using a one-way Anova with a Dunnets post testanalysis at the 0.05 significant level. Compound 125 from Example 9 at30 or 100 mg/kg and compound 104 from Example 8 at 50 and 200 mg/kgshowed no significant effect on brain Aβ x-40 levels. Compound 154 fromExample 9 dosed at 100 mg/kg showed a statistically significant decreaseof the mean compared to vehicle control of 25% in brain samples.Compound 148 from Example 9 dosed at 10, 30, 60 and 100 mg/kg showed astatistically significant decrease of the mean compared to vehiclecontrol of 23%, 31%, 31%, and 40% respectively in brain samples.Compound 151 of Example 9 was also dosed at 30 mg/kg, and samples weretaken at various timepoints, and demonstrated a reduction in Aβ x-40levels for up to 12 hours in brain samples and longer in CSF. Thus,compounds 148, 151 and 154 showed a decrease in cortical brain levels ofAβ, with compound 151 demonstrating decreased levels of Aβ in both brainand CSF for as long as 12 hours.

Example C Assays to Assess Pharmaceutical Properties

Various assays can be used to evaluate other pharmaceutical properties,such as Cyp inhibition, metabolic stability, measurement of pGp bindingor as pGp substrate, solubility, cell permeability, brain penetration,and pharmacokinetic properties. For example, assays for in vitropermeability across a monolayer of MDCK cells, in vivo assay for P-gpefflux and brain penetration in an FVB mouse model, and in vivo oralavailability in Sprague-Dawley rats are well known in the art. Compoundsas described herein have little or no Cyp inhibition or pGp binding ordo not act as pGp substrates, are relatively metabolically stable andshow good oral availability and good brain penetration.

The disclosures in this document of all articles and references,including patents, are incorporated herein by reference in theirentirety.

1: A compound having a structure according to Formula I:

or a pharmaceutically accept able salt thereof, wherein: Y is S; L is—NR⁹—; A₁ is a C₃₋₁₀ carbocyclic ring or a 3 to 10 membered heterocyclicring; A₂ is phenyl, naphthyl, or a heteroaryl ring; A₃ is phenyl,naphthyl, or a heteroaryl ring; R¹ is hydrogen, C₁₋₆ alkyl, or combineswith R² to form a fused monocyclic C₃₋₇ carbocyclic ring or a 3 to 7membered heterocyclic ring; R² and R³ are independently hydrogen orhalogen, or R³ is hydrogen and R² combines with R¹ to form a fusedmonocyclic C₃₋₇ carbocyclic ring or a 3 to 7 membered heterocyclic ring;R⁴ at each occurrence is independently selected from the groupconsisting of halogen, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, —OH, ═O, —OR¹², —S(O)_(z)R¹², —C(O)R¹², —NR¹³R¹⁴, and ═NR¹⁴,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkylare optionally substituted with one or more fluoro, —OH, —NH₂, —OR^(a),—S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b), or optionally fluorosubstituted C₃₋₆ cycloalkyl; R⁵ and R⁶ at each occurrence areindependently selected from the group consisting of halogen, —CN, —OH,—NH₂, —NO₂, —C(O)—OH, —C(O)—NH₂, —S(O)₂—NH₂, and L₁-R¹⁵; R⁹ is selectedfrom the group consisting of hydrogen and C₁₋₆ alkyl; L₁ at eachoccurrence is independently selected from the group consisting of adirect bond, —C(O)—, —O—, —S(O)_(Z), —NR¹⁶—, —C(O)—O—, —O—C(O)—,—C(O)—NR¹⁶—, —NR¹⁶—C(O)—, —S(O)₂—NR¹⁶—, and —NR¹⁶—S(O)₂—; R¹² at eachoccurrence is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl areoptionally substituted with one or more substituents independentlyselected from the group consisting of fluoro, —OH, —NH₂, —OR^(a),—S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b), and optionallyfluoro substituted C₃₋₆ cycloalkyl; R¹³ and R¹⁴ at each occurrence areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl areoptionally substituted with one or more substituents independentlyselected from the group consisting of fluoro, —OH, —NH₂, —OR^(a),—S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b), and optionallyfluoro substituted C₃₋₆ cycloalkyl or R¹³ and R¹⁴ combine with thenitrogen to which they are attached to form a 4-7 membered monocyclicheterocyclic ring or a 5 or 7 membered heteroaryl ring, wherein saidring is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, —CN, ═O,—OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b),and optionally fluoro substituted C₁₋₆ alkyl, optionally fluorosubstituted C₂₋₆ alkenyl, optionally fluoro substituted C₂₋₆ alkynyl,and optionally fluoro substituted C₃₋₆ cycloalkyl; R¹⁵ at eachoccurrence is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl, 3-7 memberedheterocycloalkyl, phenyl, naphthyl, and heteroaryl, wherein phenyl,naphthyl, and heteroaryl are optionally substituted with one or moresubstituents independently selected from the group consisting of —CN,—OH, —NO2, —C(O)—OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 memberedheteroaryl, —OR¹⁷, —S(O)_(z)R¹⁷, —NR¹⁸R¹⁹, —C(O)R¹⁷, —C(O)—OR¹⁷,—O—C(O)R¹⁷, —C(O)—NR¹⁸R¹⁹, —NR¹⁶—C(O)R¹⁷, —S(O)₂—NR¹⁸R¹⁹, and—NR¹⁶—S(O)₂R¹⁷, and wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, as R¹⁵ or as asubstituent of phenyl, naphthyl, or heteroaryl, are optionallysubstituted with one or more substituents independently selected fromthe group consisting of fluoro, —CN, —OH, ═O, ═NH, —NO₂, —C(O)—OH, C₃₋₆cycloalkyl, 3-7 membered heterocycloalkyl, —OR¹⁷, —S(O)_(z)R¹⁷, ═NR¹⁷,—NR¹⁸R¹⁹, —C(O)R¹⁷, —C(O)—OR¹⁷, —O—C(O)R¹⁷, —C(O)—NR¹⁸R¹⁹,—NR¹⁶—C(O)R¹⁷, —S(O)₂—NR¹⁸R¹⁹, and —NR¹⁶—S(O)₂R¹⁷; R¹⁶ at eachoccurrence is independently selected from the group consisting ofhydrogen C₁₋₆ alkyl; R¹⁷ at each occurrence is independently selectedfrom the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₃₋₆ cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₃₋₆ cycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of fluoro,—OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b),and optionally fluoro substituted C₃₋₆ cycloalkyl; R¹⁸ and R¹⁹ at eachoccurrence are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkylare optionally substituted with one or more substituents independentlyselected from the group consisting of fluoro, —OH, —NH₂, —OR^(a),—S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b), and optionallyfluoro substituted C₃₋₆ cycloalkyl, or R¹⁸ and R¹⁹ combine with thenitrogen to which they are attached to form a 4-7 membered monocyclicheterocyclic ring or a 5 or 7 membered heteraoryl ring, wherein saidring is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, —CN, ═O,—OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b),optionally fluoro substituted C₁₋₆ alkyl, optionally fluoro substitutedC₂₋₆ alkenyl, optionally fluoro substituted C₂₋₆ alkynyl, and optionallyfluoro substituted C₃₋₆ cycloalkyl; R^(a) and R^(b) at each occurrenceare independently selected from the group consisting of optionallyfluoro substituted C₁₋₆ alkyl, optionally fluoro substituted C₂₋₆alkenyl, optionally fluoro substituted C₂₋₆ alkynyl, and optionallyfluoro substituted C₃₋₆ cycloalkyl, or R^(a) and R^(b) combine with thenitrogen to which they are attached to form N-linked-heterocycloalkyl; mis 0, 1, or 2; n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; and z is 0, 1, or2.
 2. The compound of claim 1, wherein the compound has the followingformula:

or a pharmaceutically acceptable salt thereof, wherein: X is O or S(O)₂,r is 0, 1, or 2; and s is 0, 1, or
 2. 3. The compound of claim 2,wherein X is O.
 4. The compound of claim 3, wherein the compound has thestructure:


5. The compound of claim 1, wherein A₁ is 3 to 10 membered heterocyclicring.
 6. The compound of claim 1, wherein A₂ is phenyl.
 7. The compoundof claim 1, wherein A₃ is a heteroaryl ring.
 8. The compound of claim 1,wherein R¹ is a C₁₋₆ alkyl.
 9. The compound of claim 1, wherein R² andR³ are independently hydrogen or a halogen.
 10. The compound of claim 1,wherein R⁴ at each occurrence is a halogen.
 11. The compound of claim 1,wherein R⁶ at each occurrence L₁-R¹⁵.
 12. The compound of claim 11,wherein L₁ is —O— and R¹⁵ is a C₁₋₆ alkyl.
 13. The compound of claim 1,wherein R⁹ is hydrogen.
 14. The compound of claim 1, wherein m is 1 or2.
 15. The compound of claim 1, wherein n is 1 and R⁵ is a halogen. 16.The compound of claim 1, wherein p is 1 and R⁶ is L₁-R¹⁵, wherein L₁ is—O— and R¹⁵ is methyl.
 17. The compound of claim 2, wherein X is O; r is0; s is 0; A₂ is phenyl; and A₃ is pyridinyl.
 18. The compound of claim16, wherein n is 1 and R⁵ is a halogen.
 19. A compound having astructure according to Formula I:

or a pharmaceutically accept able salt thereof, wherein: Y is S; L is—NR⁹—C(O)—; A₁ is a C₃₋₁₀ carbocyclic ring or a 3 to 10 memberedheterocyclic ring; A₂ is phenyl, naphthyl, or a heteroaryl ring; A₃ isphenyl, naphthyl, or a heteroaryl ring; R¹ is hydrogen, C₁₋₆ alkyl, orcombines with R² to form a fused monocyclic C₃₋₇ carbocyclic ring or a 3to 7 membered heterocyclic ring; R² and R³ are independently hydrogen orhalogen, or R³ is hydrogen and R² combines with R¹ to form a fusedmonocyclic C₃₋₇ carbocyclic ring or a 3 to 7 membered heterocyclic ring;R⁴ at each occurrence is independently selected from the groupconsisting of halogen, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, —OH, ═O, —OR¹², —S(O)_(z)R¹², —C(O)R¹², —NR¹³R¹⁴, and ═NR¹⁴,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkylare optionally substituted with one or more fluoro, —OH, —NH₂, —OR^(a),—S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b), or optionally fluorosubstituted C₃₋₆ cycloalkyl; R⁵ and R⁶ at each occurrence areindependently selected from the group consisting of halogen, —CN, —OH,—NH₂, —NO₂, —C(O)—OH, —C(O)—NH₂, —S(O)₂—NH₂, and L₁-R¹⁵; R⁹ is selectedfrom the group consisting of hydrogen and C₁₋₆ alkyl; L₁ at eachoccurrence is independently selected from the group consisting of adirect bond, —C(O)—, —O—, —S(O)_(Z), —NR¹⁶—, —C(O)—O—, —O—C(O)—,—C(O)—NR¹⁶—, —NR¹⁶—C(O)—, —S(O)₂—NR¹⁶—, and —NR¹⁶—S(O)₂—; R¹² at eachoccurrence is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl areoptionally substituted with one or more substituents independentlyselected from the group consisting of fluoro, —OH, —NH₂, —OR^(a),—S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b), and optionallyfluoro substituted C₃₋₆ cycloalkyl; R¹³ and R¹⁴ at each occurrence areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl areoptionally substituted with one or more substituents independentlyselected from the group consisting of fluoro, —OH, —NH₂, —OR^(a),—S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b), and optionallyfluoro substituted C₃₋₆ cycloalkyl or R¹³ and R¹⁴ combine with thenitrogen to which they are attached to form a 4-7 membered monocyclicheterocyclic ring or a 5 or 7 membered heteroaryl ring, wherein saidring is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, —CN, ═O,—OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b),and optionally fluoro substituted C₁₋₆ alkyl, optionally fluorosubstituted C₂₋₆ alkenyl, optionally fluoro substituted C₂₋₆ alkynyl,and optionally fluoro substituted C₃₋₆ cycloalkyl; R¹⁵ at eachoccurrence is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl, 3-7 memberedheterocycloalkyl, phenyl, naphthyl, and heteroaryl, wherein phenyl,naphthyl, and heteroaryl are optionally substituted with one or moresubstituents independently selected from the group consisting of —CN,—OH, —NO2, —C(O)—OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 memberedheteroaryl, —OR¹⁷, —S(O)_(z)R¹⁷, —NR¹⁸R¹⁹, —C(O)R¹⁷, —C(O)—OR¹⁷,—O—C(O)R¹⁷, —C(O)—NR¹⁸R¹⁹, —NR¹⁶—C(O)R¹⁷, —S(O)₂—NR¹⁸R¹⁹, and—NR¹⁶—S(O)₂R¹⁷, and wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, as R¹⁵ or as asubstituent of phenyl, naphthyl, or heteroaryl, are optionallysubstituted with one or more substituents independently selected fromthe group consisting of fluoro, —CN, —OH, ═O, ═NH, —NO₂, —C(O)—OH, C₃₋₆cycloalkyl, 3-7 membered heterocycloalkyl, —OR¹⁷, —S(O)_(z)R¹⁷, ═NR¹⁷,—NR¹⁸R¹⁹, —C(O)R¹⁷, —C(O)—OR¹⁷, —O—C(O)R¹⁷, —C(O)—NR¹⁸R¹⁹,—NR¹⁶—C(O)R¹⁷, —S(O)₂—NR¹⁸R¹⁹, and —NR¹⁶—S(O)₂R¹⁷; R¹⁶ at eachoccurrence is independently selected from the group consisting ofhydrogen C₁₋₆ alkyl; R¹⁷ at each occurrence is independently selectedfrom the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₃₋₆ cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₃₋₆ cycloalkyl are optionally substituted with one or moresubstituents independently selected from the group consisting of fluoro,—OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b),and optionally fluoro substituted C₃₋₆ cycloalkyl; R¹⁸ and R¹⁹ at eachoccurrence are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆ cycloalkylare optionally substituted with one or more substituents independentlyselected from the group consisting of fluoro, —OH, —NH₂, —OR^(a),—S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b), and optionallyfluoro substituted C₃₋₆ cycloalkyl, or R¹⁸ and R¹⁹ combine with thenitrogen to which they are attached to form a 4-7 membered monocyclicheterocyclic ring or a 5 or 7 membered heteraoryl ring, wherein saidring is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, —CN, ═O,—OH, —NH₂, —OR^(a), —S(O)_(z)R^(a), —C(O)R^(a), —NHR^(a), —NR^(a)R^(b),optionally fluoro substituted C₁₋₆ alkyl, optionally fluoro substitutedC₂₋₆ alkenyl, optionally fluoro substituted C₂₋₆ alkynyl, and optionallyfluoro substituted C₃₋₆ cycloalkyl; R^(a) and R^(b) at each occurrenceare independently selected from the group consisting of optionallyfluoro substituted C₁₋₆ alkyl, optionally fluoro substituted C₂₋₆alkenyl, optionally fluoro substituted C₂₋₆ alkynyl, and optionallyfluoro substituted C₃₋₆ cycloalkyl, or R^(a) and R^(b) combine with thenitrogen to which they are attached to form N-linked-heterocycloalkyl; mis 0, 1, or 2; n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; and z is 0, 1, or2.
 20. The compound of claim 19, wherein the compound has the followingformula:

or a pharmaceutically acceptable salt thereof, wherein: X is O or S(O)₂;r is 0, 1, or 2; and s is 0, 1, or
 2. 21. The compound of claim 20,wherein X is O.
 22. The compound of claim 21, wherein the compound hasthe structure:


23. The compound of claim 19, wherein A₁ is 3 to 10 memberedheterocyclic ring.
 24. The compound of claim 19, wherein A₂ is phenyl.25. The compound of claim 19, wherein A₃ is a heteroaryl ring.
 26. Thecompound of claim 19, wherein R¹ is a C₁₋₆ alkyl.
 27. The compound ofclaim 19, wherein R² and R³ are independently hydrogen or a halogen. 28.The compound of claim 19, wherein R⁴ at each occurrence is a halogen.29. The compound of claim 19, wherein R⁵ at each occurrence is ahalogen.
 30. The compound of claim 19, wherein R⁶ at each occurrence isa halogen.
 31. The compound of claim 19, wherein R⁹ is hydrogen.
 32. Thecompound of claim 19, wherein m is 1 or
 2. 33. The compound of claim 19,wherein n is 1 and R⁵ is a halogen.
 34. The compound of claim 19,wherein p is 1 and R⁶ is a halogen.
 35. The compound of claim 20,wherein X is O; r is 0; s is 0; A₂ is phenyl; and A₃ is pyridinyl. 36.The compound of claim 20, wherein n and p are each 1, and R⁵ and R⁶ areeach a halogen.